maladies du sang, Lille, France,

Istituto Nazionale Tumori Regina

Elena di Roma, Ematologia, Roma, Italy,

University of Torino, A.O.U.

"Città della Salute e della Scienza di Torino", Division of Hematology,

Department of Molecular Biotechnologies and Health Sciences, Torino,

Italy,

Azienda sanitaria locale Biella, Ospedale degli Infermi ‐Ema-

tologia, Biella, Italy,

CHU de Nantes ‐Hôtel Dieu, Service d'héma-

tologie clinique, Nantes, France,

CLCC Henri Becquerel, Service

d'Hématologie, ROUEN, France,

Azienda Ospedaliera Nazionale SS.

Antonio e Biagio e C. Arrigo, SC Ematologia, Alessandria, Italy,

Ospedale Oncologico, Struttura complessa di Ematologia e CTMO,

Cagliari, Italy,

Azienda USL Toscana nord ovest, Ospedali Riuniti

Livorno ‐Ematologia, Livorno, Italy,

Presidio Ospedaliero “Andrea

Tortora” di Pagani, Ematologia, Pagani, Italy,

Ospedale Infermi di

Rimini, Ematologia, Rimini, Italy,

Università La Sapienza ‐Policlinico

Umberto I, Dipartimento di Medicina Traslazionale e di Precisione,

Roma, Italy,

Lymphoma Unit, Oncology and Hematology, Pescara,

Italy,

CHU Montpellier, Hématologie clinique, Montpellier, France,

CHU Dijon Bourgogne, Hematologie Clinique, Dijon, France,

Fon-

dazione IRCCS Istituto Nazionale dei Tumori, S.C. Ematologia, Milano,

Italy,

HenriMondor University Hospital, APHP, Lymphoid Malig-

nancies Unit, Crétiel, France,

CHU de Rennes, Hématologie clinique,

Rennes, France,

Azienda Ospedaliera Santa Maria Terni, SCU

Oncoematologia, Terni, Italy,

Azienda USL Toscana sud est, Emato-

logia ‐Ospedale San Donato, Arezzo, Italy,

ASST Sette Laghi, Ospe-

dale di Circolo e Fondazione Macchi ‐Ematologia, Varese, Italy,

IRCCS CROB, Ematologia, Rionero in Vulture, Italy,

Azienda

Ospedaliero Universitaria di Parma, Ematologia e Centro trapianti

midollo osseo, Parma, Italy,

Centro Riferimento Oncologico, Divisione

di Oncologia Medica A, Aviano, Italy,

Foundation for the Institute of

Oncology Research (IOR), International Extranodal Lymphoma Study

Group, Bellinzona, Switzerland,

Università della Svizzera Italiana,

Institute of Oncology Research, Bellinzona, Switzerland,

Foundation

for the Institute of Oncology Research (IOR), International Extranodal

Lymphoma Study Group, Oncology Institute of Southern Switzerland,

Medical Oncology Clinic, Bellinzona, Switzerland,

Oncology Institute

of Southern Switzerland, Medical Oncology Clinic, Bellinzona,

Switzerland,

AP‐HP ‐Hôpital Saint‐Louis, Service d'Hématologie‐

Oncologie, Paris, France

Introduction: The International Extranodal Lymphoma Study Group

(IELSG), in collaboration with the Italian Lymphoma Foundation (FIL)

and the Lymphoma Study Association (LYSA), conducted the IELSG38

trial to evaluate the role of rituximab maintenance in mucosa asso-

ciated lymphoid tissue (MALT) lymphoma patients (pts) after the

administration of a front‐line rituximab‐chlorambucil regimen. In a

prior study (IELSG19), this regimen, without maintenance, produced

superior event‐free (EFS) and progression‐free survival (PFS) in

comparison to either agent alone.

Methods: Pts with MALT lymphoma arisen at any extranodal site, de

novo, or relapsed following local therapy and/or antibiotics were

eligible.

Treatment consisted of an induction phase with chlorambucil (6 mg/

m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22)

and rituximab (375 mg/m2 intravenously on day 1 of week 1, 2, 3, 4

and 1400 mg subcutaneously on week 9, 13, 17, and 21). Pts with

complete (CR), partial response (PR) or stable disease were eligible

for maintenance with subcutaneous rituximab 1400 mg every two

months for two years.

Results: The study completed its planned accrual enrolling 112 pa-

tients, 53 women and 59 men (median age 65 years; range 32‐86).

Primary lymphoma localization was gastric in 32% and non‐gastric in

68% of pts. Over half of pts (56%) had advanced disease (stage III‐IV).

MALT IPI showed low risk in 29%, intermediate risk in 40% and high

risk in 30%.

Twenty‐four pts did not complete study treatment. Fifteen ceased

before maintenance: 4 due to drug related (DR) adverse events

(AEs), 3 to non‐DR AEs, 2 to high grade transformation, 1 each for

progressive disease (PD), second tumor, protocol deviation, inves-

tigator decision, patient decision, consent withdrawal. Nine dis-

continued during maintenance (3 DR AEs, 2 PD, 2 second tumors,

1 patient decision, 1 protocol deviation). The most common AEs of

grade≥3 were hematologic (neutropenia in 33%, lymphocytopenia

in 16%, leukopenia in 14%). Five pts experienced DR serious AEs

(fever of unknown origin, sepsis, pneumonia, acute respiratory

distress syndrome and progressive multifocal leukoencephalop-

athy). Best response was CR in 87% of pts. In the intention‐to‐

treat population, CR rate increased over time from 53% at the

end of induction to 65% at the end of maintenance. With a median

follow‐up of 65 months (IQR, 58‐69), median EFS, PFS and OS

were not reached. The 5‐year EFS, PFS and OS were respectively

76% (95%CI, 67‐83%), 87% (95%CI, 79‐92%) and 93% (95%CI, 86‐

96%).

Conclusions: IELSG38 is the ﬁrst trial that speciﬁcally evaluated

subcutaneous rituximab maintenance in patients with MALT

lymphoma. No new safety signals were identiﬁed. Long‐term dis-

ease control was achieved in the majority of patients and,

despite the inclusion of more high risk patients (30% vs. 17%), the

5 year PFS (87% vs. 72%) compared favorably with the IELSG19

trial.

132

SUPPLEMENT ABSTRACTS

The research was funded by: F. Hoffmann‐La Roche Ltd, Basel pro-

vided the drug rituximab free of charge and partially supported the

study ﬁnancially.

Keywords: Chemotherapy Combination, Therapies Immunotherapy

Conﬂicts of interests pertinent to the abstract

P. Feugier

Consultant or advisory role: Roche

Educational grants: Roche

F. Merli

Consultant or advisory role: Roche

Educational grants: Roche

E. Gyan

Consultant or advisory role: Roche

F. Morschhauser

Consultant or advisory role: Roche

A. Pulsoni

Consultant or advisory role: Roche, Merck, Pﬁzer, Sandoz, Takeda,

Gylead, Bristol Myers Squibb

G. Cartron

Consultant or advisory role: Roche, Celgene‐BMS

Honoraria: Sanoﬁ, Celgene, Gilead, Novartis, Roche, Abbvie

O. Casasnovas

Consultant or advisory role: Roche, Takeda, MSD, BMS, Gilead

Honoraria: Roche, Takeda, MSD, BMS, Gilead

Research funding: Roche, Gilead

Educational grants: Roche, Amgen

C. Haioun

Consultant or advisory role: Roche

Honoraria: Roche

A. M. Liberati

Consultant or advisory role: Servier

Research funding: Novartis, Janssen, Abbvie, Roche, Amgen, Celgene,

BMS, Takeda, Incyte, Beigene, Oncopeptides AB, Verastem, Kar-

yopharm, Archigen, Debiopharm International, Morphosys, Fibrogen,

Onconova Therapeutics Inc

D. Rossi

Honoraria: Abbvie, Astra Zeneca, Janssen

Research funding: Abbvie, Astra Zeneca, Janssen

S. Luminari

Consultant or advisory role: Rochem, Janssen, BMS, Regeneron,

Genmab, Incyte

Educational grants: Janssen, BMS

A. Stathis

Consultant or advisory role: Roche, Bayer, Eli LIlly

Research funding: Merck, Bayer, Roche, Novartis, Pﬁzer, ADC The-

arapeutics, MEW Pharma, Eli Lilly

C. Thieblemont

Consultant or advisory role: Roche, Incyte, Janssen, Gilead, Kyte,

Novartis

080 |RESPONSE ADAPTED POST INDUCTION THERAPY

IN FOLLICULAR LYMPHOMA: UPDATED RESULTS OF

THE FOLL12 TRIAL BY THE FONDAZIONE ITALIANA LINFOMI

(FIL)

S. Luminari

, S. Galimberti

, A. Versari

, A. Tucci

, C. Boccomini

L. Farina

, F. Zaja

, L. Marcheselli

, S. Ferrero

, L. Arcaini

A. Pulsoni

, G. Musuraca

, C. Califano

, M. Merli

, A. Bari

A. Conconi

, I. del Giudice

, F. Re

, P. M. Stefani

, S. V. Usai

T. Perrone

, G. Gini

, B. Falini

, V. Gattei

, M. Manni

M. Ladetto

, D. Mannina

, M. Federico

Azienda Unità Sanitaria Locale IRCCS, Arcispedale Santa Maria

Nuova IRCCS, Hematology Unit and, University of Modena and Reggio

Emilia, Surgical, Medical and Dental Department of Morphological

Sciences related to Transplant, Oncology and Regenerative Medicine,

Reggio Emilia, Italy,

University of Pisa, Department of Clinical and

Experimental Medicine, Pisa, Italy,

Azienda Unità Sanitaria Locale‐

IRCCS ‐Arcispedale Santa Maria Nuova, Medicina Nucleare, Reggio

Emilia, Italy,

ASST Spedali Civili di Brescia, SC Ematologia, Brescia,

Italy,

A.O.U. Città della Salute e della Scienza di Torino, SC Emato-

logia, Torino, Italy,

Fondazione IRCCS Istituto Nazionale dei Tumori di

Milano, Division of Hematology, Milano, Italy,

Università degli Studi

di Trieste, Dipartimento Clinico di Scienze mediche, chirurgiche e della

salute and, Azienda Sanitaria Universitaria Giuliano Isontina, SC

Ematologia, Trieste, Italy,

Fondazione Italiana Linfomi Onlus, FIL,

Modena, Italy,

University of Torino, Hematology, Department of

Molecular Biotechnologies and Health Sciences and, AOU “Città della

Salute e della Scienza di Torino”, Hematology 1, Torino, Italy,

Fon-

dazione IRCCS Policlinico San Matteo di Pavia, Division of Hematology

and, University of Pavia, Department of Molecular Medicine, Pavia,

Italy,

Sapienza Università di Roma, Dipartimento di Biotecnologie

Cellulari ed Ematologia, Roma, Italy,

IRCCS Istituto Romagnolo per

lo Studio dei Tumori (IRST) "Dino Amadori", Department of Hema-

tology, Meldola, Italy,

Ospedale Umberto I, U.O. Medicina‐

Oncoematologia, Nocera Inferiore, Italy,

University Hospital Ospedale

di Circolo e Fondazione Macchi, ASST Settelaghi, Varese, Italy,

Università di Modena e Reggio Emilia, Dipartimento di Scienze

Mediche e Chirurgiche Materno‐Infantili e dell'Adulto, Modena, Italy,

Ospedale degli Infermi, Unit of Hematology, Biella, Italy,

Policlinico

Umberto I ‐Università "La Sapienza" ‐Istituto Ematologia, Diparti-

mento di Medicina Traslazionale e di Precisione, Roma, Italy,

Azienda Ospedaliero Universitaria di Parma, UO Ematologia e

CTMO, Parma, Italy,

General Hospital Ca' Foncello, Hematology,

Treviso, Italy,

Ospedale Oncologico Armando Businco, Division of

Hematology, Cagliari, Italy,

University of Bari, Hematology, Bari,

Italy,

Marche Polytechnic University, Department of Clinical and

Molecular Sciences, Hematology, Ancona, Italy,

Ospedale S. Maria

della Misericordia, University of Perugia, Institute of Hematology and

SUPPLEMENT ABSTRACTS

133

CREO (Center for Hemato‐Oncological Research), Perugia, Italy

Cen-

tro di Riferimento Oncologico di Aviano (CRO) IRCCS, Clinical and

Experimental Onco‐Hematology Unit, Aviano, Italy,

University of

Modena and Reggio Emilia, Surgical, Medical and Dental Department

of Morphological Sciences related to Transplant, Oncology and

Regenerative Medicine, Modena, Italy,

Università del Piemonte Ori-

entale, Dipartimento di Medicina Traslazionale and, AO SS Antonio e

Biagio e Cesare Arrigo, SC Ematologia, Alessandria, Italy,

Azienda

Ospedaliera Papardo, UOC di Ematologia, Messina, Italy

Background: Two years of rituximab maintenance (RM) after ﬁrst‐

line rituximab‐based chemotherapy signiﬁcantly improved

progression‐free survival (PFS) in patients with follicular lymphoma

(FL). However, one important question is whether this approach is

really suitable for all patients. Here, we report the results from the

FOLL12 study, comparing RM with a response adapted post‐

induction approach.

Methods: We randomly assigned treatment naïve, advanced stage,

high tumor burden FL patients to receive standard RM or a

response‐oriented post‐induction approach based on metabolic

response and molecular assessment of minimal residual disease

(MRD). End of Induction (EOI) metabolic response was centrally

deﬁned applying the 5‐point Deauville scale (DS) that deﬁned

Complete metabolic response (CMR) in case for DS 1‐3. MRD was

deﬁned according to nested PCR assessment of Bcl2/IgH rear-

rangement on bone marrow and peripheral blood and was evalu-

ated only for patients with a molecular marker (MM) at baseline

assessment. Post induction therapy in the experimental arm con-

sisted of: CMR and MRD‐patients, observation; CMR and MRD+

(EOI or Follow up) 4 weekly rituximab until MRD‐for up to 3

courses; no CMR, one dose of ibritumomab tiuxetan followed by

standard RM. The primary endpoint was 3‐year Progression Free

Survival (PFS).

Results: This analysis was conducted on 712 out of 807 randomized

patients who achieved at least a Partial response at EOI. After a

median follow‐up of 53 months (range 1 to 92), patients in the

standard arm had a signiﬁcantly better PFS than the experimental

approach (3‐year PFS 86% vs 72%, P <0.001). The improved PFS of

FIGURE 1 Progression free survival by study arm for patients’ sugroups: A) Patients with complete metabolic response (CMR) after

induction therapy; B) Patients with both CMR and complete molecular response (MRD‐); C) patients with CMR and MRD+; D) Patients

without CMR Legend to ﬁgure: A: reference arm; B: experimental arm

134

SUPPLEMENT ABSTRACTS

the standard vs experimental arm was conﬁrmed in the study sub-

groups (Figure 1); CMR patients (A) (N =628: 3‐yr PFS 90% and 72%

for standard and experimental arm, respectively (P = < 0.001); CMR

and MRD‐(B) (N =299: 92% vs 78%; P <0.001); CMR and MRD+

without CMR no difference in PFS was observed between reference

and experimental arm (P =0.274) (D).

At time of last update 30 deaths were reported, of which 15 were

associated with disease progression or recurrence. The 3‐yr OS was

98% (95%CI 96‐99) and 97% (95%CI 95‐99) in the reference and

experimental arm, respectively (p =0.238).

Conclusions: A metabolic and a molecular response adapted

therapy as assessed in the FOLL12 study was associated with a

signiﬁcantly inferior PFS compared to 2‐year rituximab mainte-

nance. The better efﬁcacy of standard RM was conﬁrmed in the

subgroup analysis and in particular for patients achieving both

CMR and MRD‐.

The research was funded by:

‐Società Italiana di Ematologia (SIE)

‐Associazione Angela Serra per la Ricerca sul Cancro

‐Ministero della Salute, Direzione Generale della ricerca e dell’In-

novazione in sanità (BANDO PROGETTI DI RICERCA GIOVANI

RICERCATORI ‐RICERCA FINALIZZATA 2011‐2012)

Keywords: Indolent non‐Hodgkin, lymphoma Combination

Therapies

No conﬂicts of interests pertinent to the abstract.

081 |IMMUNE PRIMING WITH NIVOLUMAB FOLLOWED BY

NIVOLUMAB & RITUXIMAB IN 1

LINE TREATMENT OF

FOLLICULAR LYMPHOMA: THE PHASE 2 1

FLOR STUDY

E. A. Hawkes

, S. T. Lee

, G. Chong

, M. Gilbertson

, A. Grigg

L. Churilov

, T. Fancourt

, C. Keane

, D. Ritchie

, R. Koldej

R. Agarwal

, K. Manos

, C. Smith

, K. Houdyk

, J. Hawking

A. Barraclough

Olivia Newton‐John Cancer Research and Wellness Centre, Medical

Oncology and Haematology, Melbourne, Australia,

Austin Health,

Molecular Imaging and Therapy, Melbourne, Australia,

Ballarat

Regional Intergrated Cancer Centre, Haematology and Oncology, Bal-

larat, Australia,

Monash Health, Haematology, Melbourne, Australia,

Austin Health, Haematology, Melbourne, Australia,

Melbourne Brain

Centre, Florey Institute of Neuroscience and Mental Health, Melbourne,

Australia,

Austin Health, Anatomical Pathology, Melbourne, Australia,

Princess Alexandra Hospital, Haematology, Brisbane, Australia,

Peter

MacCallum Cancer Centre and Royal Melbourne Hospital, Haematology,

Melbourne, Australia,

The Royal Melbourne Hospital, ACRF Trans-

lational Research Laboratory, Melbourne, Australia,

Austin Health,

Molecular Diagnostics, Melbourne, Australia,

Austin Health, Haema-

tology, Melbourne, Australia,

Austin Health, Cancer Clinical Trials

Centre, Melbourne, Australia,

Fiona Stanley Hospital, Haematology,

Perth, Australia

Introduction: Standard of care immunochemotherapy in front‐line

(1L) follicular lymphoma (FL) is highly efﬁcacious but not without

signiﬁcant toxicity. High rates of grade 3‐5 adverse events (AEs),

primarily infection and bone marrow suppression, are experienced in

up to 75% of patients. A more tolerable but equally effective

approach is required. PD‐1 inhibition, in combination with rituximab

(R), increases T cell anti‐tumour effect & enhances NK cell antibody

dependent cell cytotoxicity, with proven efﬁcacy in relapsed FL. The

concept of ‘priming’ the immune system with nivolumab (N) prior to

tumour‐directed therapy has rationale and evidence, but the safety

of this approach in 1L FL is not described.

Methods: ‘1

FLOR’ (NCT03245021) is an open‐label, multi‐centre,

phase 2, Simon's 2‐stage study of N +R (N =39). Key eligibility were

stage III‐IV grade 1‐3A FL requiring 1L systemic therapy; ECOG ≤2;

adequate organ function. All patients (pts) receive induction N

240mg IV 2‐weekly for 4 cycles. Pts with complete response (CR)

receive 4 further cycles of 240mg IV N monotherapy then 12 cycles

of maintenance N 480mg IV 4‐weekly. Pts with 2 IV R 2‐weekly for 4

cycles followed by maintenance N+R (N 480mg 4 weekly for 12

cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was ≥G3

toxicity rate. Secondary EPs were response rate, overall toxicity,

progression free survival (PFS) & overall survival (OS).

Results: Between September 2017 to March 2020, 39 pts were

enrolled. Baseline characteristics included median age of 54 (range:

28‐79), stage IV disease in 67%, B Symptoms & bulk (≥7cm) in 23%

each, intermediate‐high risk FLIPI in 74%.

The primary EP was met, with 16 pts (41%) having ≥G3 toxicity at

end of induction. Non‐immune AEs were predominantly G1‐2; most

commonly infection (67%) & fatigue (64%). G3‐4 Immune‐related AEs

were infrequent and included pancreatitis plus hepatitis (N =1),

pancreatitis alone (N =1), rash (N =1), transaminitis (N =2),

hypocortisolism (N =1), hyperglycaemia (N =3) and asymptomatic

lipase/amylase increase (N =3).

Median follow‐up was 17.5 months (range: 7‐39). Overall response

rate was 92% (36/39) with CR in 54% (21/39). Median time to CR

was 5 months (m) (range: 2‐25). Nine pts (23%) discontinued treat-

ment; 7 due to progressive disease (1 pt died of transformed FL), 2

developed constitutional symptoms (1 stable disease, 1 partial

response). In 25 evaluable pts, 12m PFS & OS is 72% (CI 51‐88) &

96% (CI 80‐100).

Biomarker analysis is in progress.

Conclusion: Immune‐priming with single‐agent N, then combination

N+R in 1L FL is associated with favourable toxicity and high

ORR & CR rates potentially providing an alternative to

chemotherapy.

Acknowledgements

Bristol‐myers Squibb provided funding and nivolumab for this study.

EA – previously submitted to ASCO 2021.

The research was funded by: Bristol‐myers Squibb

SUPPLEMENT ABSTRACTS

135

Keywords: Immunotherapy, Indolent non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

E. A. Hawkes

Consultant or advisory role: Antigene, Janssen, Gilead, Merck Sharpe

and Dohme, Astra Zenica, Bristol Myers Squibb/Celgene, Roche

Honoraria: Roche, AstraZenica, Janssen

Research funding: Roche, Bristol Myers Squibb/Celgene, Merck KgA,

Astra Zenica,

Educational grants: Roche, Janssen

G. Chong

Consultant or advisory role: Bristol Myers Squibb

Research funding: Bristol Myers Squibb, Merck Serono, Hutchison

Medipharma, Regeneron, AstraZeneca, Pharmacyclics, Bayer, Servier,

Isofol

A. Grigg

Consultant or advisory role: Janssen, Sylvant

Honoraria: MSD, Gilead, Roche, Novartis

C. Keane

Consultant or advisory role: MSD, Celgene, Gilead Sciences, Roche,

Janssen

Honoraria: Gilead Sciences, Roche, Celgene, MDS oncology

Research funding: Bristol Myers Sqibb

Educational grants: Roche, MSD oncology, Celgene, Gilead Sciences

R. Koldej

Research funding: CRISPR Therapeutics

Educational grants: NanoString Technologies

K. Manos

Educational grants: Bristol‐Myers Squibb

A. Barraclough

Educational grants: Roche

SESSION 13: CAR‐T CELL THERAPY

082 |CAR‐HEMATOTOX: A DISCRIMINATIVE MODEL FOR CAR

T‐CELL RELATED HEMATOTOXICITY IN RELAPSED/REFRACTORY

LARGE B‐CELL LYMPHOMA

K. Rejeski

, A. Perez

, P. Sesques

, C. Berger

, L. Jentzsch

D. Mougiakakos

, L. Frölich

, J. Ackermann

, V. Bücklein

V. Blumenberg

, C. Schmidt

, L. Jallades

, B. Fehse

, C. Faul

P. Karschnia

, O. Weigert

, M. Dreyling

, E. Hoster

, F. Locke

M. von Bergwelt‐Baildon

, A. Mackensen

, W. Bethge

, F. Ayuk

E. Bachy

, G. Salles

, M. Jain

, M. Subklewe

University Hospital of the LMU Munich, Department of Hematology/

Oncology, Munich, Germany,

Mofﬁtt Cancer Center, Department of

Blood and Marrow Transplant and Cellular Immunotherapy, Mofﬁtt

Cancer Center, Tampa, USA, Tampa, USA,

Hospices Civils de Lyon,

Institut National de la Santé et de la Recherche Médicale (INSERM),

Lyon, France,

University Hospital Hamburg‐Eppendorf, Department of

Hematology, Oncology and Pulmonology, Hamburg, Germany,

Univer-

sity Hospital Tübingen, Department of Hematology, Oncology, Immu-

nology and Rheumatology, Tübingen, Germany,

University Hospital of

Erlangen, Department of Internal Medicine 5, Hematology and

Oncology, Erlangen, Germany,

University Hospital of the LMU Munich,

Department of Neurosurgery, Munich, Germany,

LMU Munich, Insti-

tute for Medical Informatics, Biometry and Epidemiology, Munich,

Germany,

MSKCC, Lymphoma Service, Department of Medicine, NYC,

New York, USA

Background: Hematotoxicity represents a frequent CAR T‐cell

related adverse event that remains poorly understood. Prolonged

cytopenia and aplastic courses can predispose for severe infectious

complications, which represent the most common cause of non‐

relapse mortality after CAR T‐cell therapy.

Methods: In this multicenter retrospective analysis, we studied

patterns of hematopoietic reconstitution and evaluated potential

predictive markers in 258 patients receiving Axicabtagene cil-

oleucel (Axi‐cel, n =170) or Tisagenlecleucel (Tisa‐cel, n =88)

for relapsed/refractory large B‐cell lymphoma. Cytopenia was

graded according to CTCAE criteria with further sub‐

characterization of neutropenia as severe (ANC <500/µl), pro-

found (ANC <100/µl), protracted (≥7 days) and prolonged (ANC <

1000/µl after day 21). We studied the impact of baseline ( =prior

to lymphodepletion) clinical and laboratory markers on hematotox-

icity by uni‐& multivariate analysis using a binary logistic

regression analysis for the outcome of severe neutropenia ≥14

days ( =Test group) vs. <14 days ( =Control group). A discrim-

inative model termed CAR‐HEMATOTOX was developed. Receiver

operator characteristic (ROC) analyses were used to assess mea-

sures of performance (sensitivity, speciﬁcity, AUC).

Results: Across all studied patients, we observed a high incidence

of profound and prolonged neutropenia of 72 and 64% respec-

tively (see Table). The incidence of severe neutropenia was 91%

with a median duration of 9 days (95% CI: 8 – 10 days). Uni‐and

multivariate analysis revealed an association between markers

associated with hematopoietic reserve (e.g. platelet count, ANC,

hemoglobin), baseline inﬂammatory state (e.g. ferritin, CRP), and

longer duration of neutropenia. In contrast, neither CRS/ICANS

grade nor peak cytokine levels were associated with long

neutropenia.

To develop the CAR‐HEMATOTOX model in our training cohort (n

=58), the discriminatory threshold for each variable signiﬁcantly

associated with hematotoxicity was determined on the basis of

optimizing the respective Youden J statistic. Additional weighting

of factors identiﬁed by stepwise multivariate analysis using a

backward elimination was applied. We validated the model in two

independent cohorts from Europe (n =91) and the USA (n =109)

and identiﬁed patients with severe neutropenia ≥14 days in both

(AUC =0.77‐0.91, P <0.001, Sensitivity 84‐100%, Speciﬁcity 67‐

69%). A high CAR‐HEMATOTOX score resulted in a longer

136

SUPPLEMENT ABSTRACTS

duration of neutropenia (12 vs. 5.5 days, P <0.001) and

discriminated for patients with aplastic features.

Conclusion: These ﬁndings underline the strikingly high incidence of

hematotoxicity after CAR T‐cell therapy. The CAR‐HEMATOTOX will

be useful for risk‐adapted management of hematotoxicity, to guide

prophylactic antimicrobial strategies, and to identify patients for

potential autologous stem cell back‐up.

Keywords: Risk Models, Cellular therapies, Aggressive B‐cell non‐

Hodgkin lymphoma

No conﬂicts of interests pertinent to the abstract.

083 |EARLY PET RESPONSE PREDICTS OUTCOME IN LARGE B‐

CELL LYMPHOMA PATIENTS TREATED WITH CD19 CAR‐T

M. Cuadrado

, T. Menne

, G. Petrides

, W. Osborne

, V. Potter

R. Benjamin

, P. Patten

, D. Yallop

, R. Sanderson

, N. Mulholland

A. Kuhnl

King's College Hospital, Haematology, London, UK,

Freeman Hospital

Newcastle, Haematology, Newcastle, UK,

Freeman Hospital, Nuclear

Medicine, Newcastle, UK,

King's College Hospital, Nuclear Medicine,

London, UK

Background: Among patients with large B‐cell lymphoma responding

to CD19 CAR‐T, about half will only have transient response and

relapse within 6 months of treatment. It is unclear which patient or

disease factors determine short‐vs. long‐term response to CAR‐T

and how to deﬁne suboptimal response requiring additional treat-

ment. We assessed early FDG PET response as predictor of outcome

after CD19 CAR‐T in lymphoma.

Methods: We analysed 90 patients with relapsed/refractory large B‐

cell lymphoma treated with licenced CD19 CAR‐T across 2 UK

centres (King's College Hospital London and Freeman Hospital

Newcastle) between February 2019 and December 2020 who were

evaluable for response at 1 and 3 months. Response was assessed

using the 5‐point Deauville score (DS) as per standard practice. The

median follow‐up for living patients was 16 months.

Results: Of 90 infused patients, 71 (79%) were treated with axi-

cabtagene ciloleucel and 19 (21%) with tisagenlecleucel. Patients’

median age was 57 years (range 18 ‐77). 55 (61%) had de novo

DLBCL, 29 (32%) transformed lymphoma, and 6 (7%) primary

mediastinal B‐cell lymphoma. 64 (71%) had advance stage, 25

(28%) bulky disease, and 51 (57%) extranodal involvement at

baseline. 78/90 (86%) patients received bridging therapy prior to

CAR‐T.

66/90 (73%) of patients showed response to CAR‐T at the 1‐month

response assessment: 31 (33%) complete response (CR, DS 1: n =

10, DS 2: n =8; DS 3: n =13), and 35 (38%) partial response (PR, DS

4: n =27, DS 5: n =8). 2 (2%) patients had stable disease (SD) and 22

(25%) had progressive disease (PD) at 1 month. Deauville response

levels were not associated with the histological subtype, double‐hit

status, stage/bulk at presentation, number of prior treatment lines,

response to last treatment, type of bridging therapy, or LDH and

ECOG PS pre‐infusion.

DS response categories at 1 month were signiﬁcantly associated with

the risk of early progression at 3 months (p <0.0001): 22% for DS 1‐

2, 46% for DS 3, 33% DS 4 and 100% for DS 5 and patients with SD

(see ﬁgure). The 12‐months progression‐free survival (PFS) was 72%

(95% CI 51‐93) for patients with DS 1‐2, 54% (95% CI 39‐70) for DS

3‐4 and 0% for DS 5 (p <0.0001). Deauville response at 1 month

remained signiﬁcant for PFS in multivariate analysis adjusting for

ECOG PS, LDH, stage, extranodal involvement and bulk. Overall

survival (OS) at 12 months for DS 1‐2, DS 3‐4, and DS 5 was 81%

(95% CI 63‐99), 64% (95% CI 48‐81), and 45% (95% CI 9‐83),

respectively (p =0.097).

Discussion: Our results indicate that early PET response using

Deauville criteria may be used to predict the risk of CAR‐T failure

TABLE 1Clinical features of CAR T‐cell related hematotoxicity by CAR T‐cell product and by CAR‐HEMATOTOX score. Statistical

signiﬁcance between groups was determined by Fisher’s exact two‐sided t test

SUPPLEMENT ABSTRACTS

137

and to guide post‐CAR‐T management in lymphoma. While patients

achieving early DS 1‐2 remission show excellent long‐term outcomes,

patients with DS 3‐4 might beneﬁt from combination approaches

within clinical trials to increase the chance of ongoing remission.

Patients with DS 5 response had dismal outcome in our cohort and

should be regarded primary treatment failure for which early ther-

apeutic intervention might be warranted.

Keywords: PET‐CT

Conﬂicts of interests pertinent to the abstract

T. Menne

Consultant or advisory role: Kite/Gilead, Amgen, Novartis, Pﬁzer,

Celgene, Daiichi Sankyo, Atara

Honoraria: Kite/Gilead, Takeda, Janssen, Roche, Servier, Novartis

Research funding: Janssen, Astra Zeneca, Novartis

W. Osborne

Honoraria: Roche, Takeda, Pﬁzer, Servier, Kite Gilead, MSD, Novartis,

Beigene, AstraZeneca, Syneos, Autolus

P. Patten

Honoraria: Novartis and Kite/Gilead

R. Sanderson

Honoraria: Novartis and Kite/Gilead

A. Kuhnl

Honoraria: Novartis, and Kite

084 |FIRST RESULTS OF DLBCL PATIENTS TREATED WITH

CAR‐T CELLS AND ENROLLED IN DESCAR‐T REGISTRY, A

FRENCH REAL‐LIFE DATABASE FOR CAR‐T CELLS IN

HEMATOLOGIC MALIGNANCIES

S. Le Gouill

, E. Bachy

, R. Di Blasi

, G. Cartron

, D. Beauvais

F. Le Bras

, François‐X. Gros

, S. Choquet

, P. Bories

, Marie‐

Thérès. Rubio

, René‐O. Casasnovas

, L. Bounaix

, M. Mohty

M. Joris

, T. Gastinne

, P. Sesques

, J. J. Tudesq

F. Morschhauser

, E. Gat

, F. Broussais

, C. Thieblemont

R. Houot

CHU de Nantes, Hematology, Nantes, France,

HCL, Hematology, Lyon,

France,

Höpital Saint‐Louis ‐APHP, Hematology, PAris, France,

CHU de

Montpellier, Hematology, Montpellier, France,

CHU de Lille, Hematology,

Lille, France,

CHU Creteil, Hematology, Creteil, France,

CHU de

Bordeaux, Hematology, Bordeaux, France,

Hôpital La Pitié‐Salpetrière ‐

APHP, Hematology, Paris, France,

Oncopole de Toulouse, Hematology,

Toulouse, France,

CHU de Nancy, Hematology, Nancy, France,

CHU

de Dijon, Hematology, Dijon, France,

CHU de Clermont‐Ferrand, He-

matology, Clermont‐Ferrand, France,

Hôpital Saint‐Antoine, Hematol-

ogy, Paris, France,

CHU Amiens, Hematology, Amiens, France,

LYSARC, DESCAR‐T, LYON, France,

LYSARC, Medical, Lyon, France,

CHU de Rennes, Hematology, Rennes, France

Background: DESCAR‐T is the French national registry for patients

treated with commercial CAR‐T cells (DLBCL and ALL). DESCAR‐T

has been designed by LYSA/LYSARC and aims to collect real‐life

FIGURE 1 Outcome according to Deauville response at 1 months. (A) risk of progressions at 3 months, (B) Progression‐free

survival

138

SUPPLEMENT ABSTRACTS

data. DESCAR‐T was approved by the French authorities in 2019

and is the reference registry for CAR‐T cells reimbursement by

French health authorities. Data (patients’ characteristics, safety,

efﬁcacy and long‐term outcome…) from time of medical decision to

treat with CAR‐T cells to up to 15 years after CAR‐T cells infusion

are registered in DESCAR‐T. Several complementary registries are

also linked to DESCAR‐T database (immune‐monitoring, blood and

tumor biobanking ‐CeVi‐CART, imagery platform). We present the

ﬁrst analyses regarding DLBCL patients' characteristics and

outcome registered in DESCAR‐T.

Methods: All patients with DLBCL registered in DESCAR‐T were

eligible for the present study. All patients gave informent consent

befor DESCAR‐T registration.

Results: To date (Jan 2021), 14 out of 24 CAR‐T cells accredited

French centers have registered patients in DESCAR‐T (other centers

are being opened). The ﬁrst patient was registered in December 2019.

At the time of the analysis, 537 DLBCL patients have been registered.

CAR‐T cells product has been ordered for 517 patients of whom 463

have been infused. At the time of registration in DESCAR‐T, median

age was 63.0 years (range, 53‐70), 40.6% of patients were >65yrs and

3.5% >75yrs. Lymphoma subtypes were DLBCL (91%), PMBL (3%),

and high‐grade B‐cell lymphoma (2%). Among patients for whom CAR‐

T cells have been ordered (n =517), 313 (60.5%) were male, 76 (14.7%)

had a PS≥2, 377 (72.9%) had an advanced disease (stage III or IV), 330

(63.8%) had elevated LDH. Median number of prior lines of treatment

was 3 (range, 2 – 3) and 21% of patients have been previously trans-

planted. Median time from CAR‐T cells order to infusion was 50 days

[range, 43‐60]. Median time from leukapheresis to CAR‐T infusion was

41.1 days (range, 36‐48). Overall, 65% of patients received Axi‐cel and

35% received Tisa‐acel. Response was available in 419 infused pa-

tients. Best ORR was 70.2% (65.5% ‐74.5%). At D30 after CAR‐T cell

infusion, 157 (38%) patients achieved CR and 112 (27%) achieved PR.

Among the 157 patients who achieved a CR at D30, 96 (61%) remained

in CR at D90. The median follow‐up calculated from CAR‐T cells order

was 7.4 months (range, 5.8‐7.9) and 6m [range, 5.5‐6.2] from CAR‐T

infusion. The median OS calculated from time of CAR‐T infusion is

12.7m [range, 10.6‐NA].

Summary/Conclusion: This ﬁrst analysis from DESCAR‐T registry

seems to conﬁrm CAR‐T cells efﬁcacy in real life. Updated results

will be presented at the meeting. Overall, 537 DLBCL patients

have been registered in DESCAR‐T in 13 months. This demon-

trates that CAR‐T cells therapy has become a key treatment for R/

R DLBCL. In 2021, DESCAR‐T will be extended to MCL and

multiple myeloma.

EA ‐previously submitted to EHA 2021.

Keywords: Aggressive B‐cell non‐Hodgkin lymphoma, Cellular

therapies

Conﬂicts of interests pertinent to the abstract

S. Le Gouill

Consultant or advisory role: Gilead; Novartis

085 |EFFICACY AND SAFETY OF TISAGENLECLEUCEL (TISA‐

CEL) IN ADULT PATIENTS (PTS) WITH RELAPSED/REFRACTORY

FOLLICULAR LYMPHOMA (R/R FL): PRIMARY ANALYSIS OF THE

PHASE 2 ELARA TRIAL

N. H. Fowler

, S. J. Schuster

, M. Dickinson

, M. Dreyling

J. Martinez‐Lopez

, A. Kolstad

, J. Butler

, M. Ghosh

, L. Popplewell

J. C. Chavez

, E. Bachy

, K. Kato

, H. Harigae

, M. José Kersten

C. Andreadis

, P. A. Riedell

, A. Zia

, M. C. Morisse

C. Thieblemont

MD Anderson Cancer Center, The University of Texas MD Anderson

Cancer Center, Houston, Texas, USA,

Perelman Center for Advanced

Medicine, University of Pennsylvania, Philadelphia, USA,

Clinical

Haematology, Peter MacCallum Cancer Centre and Royal Melbourne

Hospital, Melbourne, Australia,

Medizinische Klinik III, LMU Klinikum,

Munich, Germany,

Hospital 12 De Octubre Madrid, Complutense

University, CNIO, Madrid, Spain,

Department of Oncology, Oslo

University Hospital, Oslo, Norway,

Haematology and Bone Marrow

Transplantation, Royal Brisbane Hospital, Herston, Australia,

Department of Internal Medicine, Michigan Medicine University of

Michigan, Ann Arbor, USA,

Department of Hematology &

Hematopoietic Cell Transplantation, City of Hope National Medical

Center, Duarte, USA,

Department of Malignant Hematology, Mofﬁtt

Cancer Center, Tampa, USA,

Department of Hematology, Hospices

Civils de Lyon and Université Claude Bernard Lyon 1, Lyon, France,

Department of Hematology, Kyushu University Hospital, Fukuoka,

Japan,

Department of Hematology, Tohoku University Hospital,

Sendai, Japan,

Cancer Center Amsterdam, Amsterdam UMC,

University of Amsterdam, on behalf of HOVON/LLPC, Amsterdam,

Netherlands,

Helen Diller Family Comprehensive Cancer Center,

University of California San Francisco, San Francisco, USA,

Department of Medicine, University of Chicago, Chicago, USA,

Biostatistics, Novartis Pharma AG, Basel, Switzerland,

Oncology,

Novartis Pharmaceuticals Corporation, East Hanover, USA,

Department of Hemato‐Oncology, Hôpital Saint‐Louis‐Université de

Paris, Paris, France

Introduction: Most pts with r/r FL experience multiple relapses and

progressively worse clinical outcomes with each line of therapy,

underlining a need for novel therapies. Tisa‐cel has demonstrated

durable responses and manageable safety in adult pts with r/r diffuse

large B‐cell lymphoma. Here we report the primary analysis of

ELARA (NCT03568461), an international, single‐arm phase 2 trial of

tisa‐cel in adult pts with r/r FL.

Methods: Eligible pts (≥18 y) had r/r FL (grades [Gr] 1‐3A) after ≥2

lines of therapy or had failed autologous stem cell transplant.

Bridging therapy was permitted followed by disease assessment prior

to tisa‐cel infusion. Pts received tisa‐cel (0.6‐6�10

CAR+viable T

cells) after lymphodepleting chemotherapy. The primary endpoint

was complete response rate (CRR) by central review per Lugano

2014 criteria. Secondary endpoints included overall response rate

(ORR), duration of response (DOR), progression‐free survival (PFS),

SUPPLEMENT ABSTRACTS

139

overall survival (OS), safety, and cellular kinetics. Predeﬁned primary

analysis occurred when ≥90 treated pts had ≥6 mo of follow‐up.

Results: As of September 28, 2020, 98 pts were enrolled and 97

received tisa‐cel (median follow‐up, 10.6 mo). At study entry, median

age among treated pts was 57 y (range, 29‐73), 85% had stage III‐IV

disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42%

had LDH >upper limit of normal. The median number of prior

therapies was 4 (range, 2‐13); 78% of pts were refractory to their last

treatment (76% to any ≥2 prior regimens) and 60% progressed

within 2 y of initial anti‐CD20–containing treatment. Of 94 pts

evaluable for efﬁcacy, the CRR was 66% (95% CI, 56‐75) and the

ORR was 86% (95% CI, 78‐92). CRRs/ORRs were comparable among

key high‐risk subgroups. Estimated DOR (CR) and PFS rates at 6 mo

were 94% (95% CI, 82‐98) and 76% (95% CI, 65‐84), respectively. Of

97 pts evaluable for safety, 65% experienced Gr ≥3 adverse events

within 8 weeks post‐infusion, most commonly neutropenia (28%) and

anemia (13%). Any‐grade cytokine release syndrome (per Lee scale)

occurred in 49% of pts (Gr ≥3, 0%). Any‐grade neurological events

(per CTCAE v4.03) occurred in 9% of pts (Gr 3, 0%; Gr 4, 1 pt and

recovered). Three pts died from progressive disease.

Cellular kinetic parameters for tisa‐cel were estimated using trans-

gene levels (by qPCR) in peripheral blood. C

max

and AUC

0‐28d

were

similar between responders (CR or partial response) and non‐

responders (stable or progressive disease). Maximum transgene

levels were reached by a median of 10 days in responders and 12.9

days in non‐responders; transgene persistence was detected up to

370 days and 187 days, respectively.

Conclusions: These data demonstrate the efﬁcacy and acceptable

safety of tisa‐cel in pts with r/r FL, including high‐risk pts after

multiple lines of prior therapy, and suggest that tisa‐cel may be a

promising therapy for pts with r/r FL.

EA – previously submitted to ASCO 2021.

The research was funded by: Novartis

Keywords: Indolent non‐Hodgkin lymphoma, Cellular therapies

Conﬂicts of interests pertinent to the abstract

S. J. Schuster

Consultant or advisory role: Celgene, Nordic Nanovector, Novartis,

Abbvie, Acerta Pharma/AstraZeneca, Alimera Sciences, BieGene,

Juno Therapeutics, Luxo Oncology, Tessa Therapeutics, Genentech/

Roche

Honoraria: Novartis, Celgene

Research funding: Novartis, Pharmacyclics, Adaptive Bio-

technologies, Merck, Genentech/Roche, Celgene, Juno Therapeutics,

Abbvie, Incyte, TG Therapeutics, DTRM

M. Dickinson

Consultant or advisory role: Novartis, BMS, Gilead Sciences, Roche,

Janssen

Honoraria: Roche, Amgen, MSD, Janssen, BMS, Novartis

Research funding: Roche, Novartis, Takeda, Celgene, MSD

Educational grants: Roche

M. Dreyling

Consultant or advisory role: Acerta Pharma/AstraZeneca, Bayer/Vi-

tal, Celgene/Jazz, Gilead Sciences, Janssen‐Cilag, Novartis, Roche,

BeiGene

Honoraria: Bayer Health, Celgene, Gilead Sciences, Janssen‐Cilag,

Roche Pharma AG

Research funding: Celgene, Janssen‐Cilag, Roche Pharma AG,

Abbvie

Educational grants: Celgene, Janssen‐Cilag, Roche Pharma AG

J. Martinez‐Lopez

Consultant or advisory role: Janssen, Novartis, BMS, Incite, Astellas,

Glaxo

Stock ownership: Altum Sequencing

Honoraria: Janssen, Novartis, BMS, Incite, Astellas, Glaxo

Research funding: BMS, Roche

A. Kolstad

Consultant or advisory role: Nordic Nanovector

Research funding: Merck, Nordic Nanovector

Educational grants: Nordic Nanovector

J. Butler

Consultant or advisory role: Novartis

Honoraria: Novartis

M. Ghosh

Research funding: Novartis, BMS

L. Popplewell

Honoraria: Roche, Pﬁzer

Educational grants: Novartis

J. C. Chavez

Consultant or advisory role: Kite/Gilead, Novartis, Bayer, Kar-

yopharm Therapeutics, Verastem, Pﬁzer, MorphoSys, TeneoBio,

Celgene, Juno Therapeutics

Honoraria: Kite/Gilead, Genentech, AstraZeneca, BeiGene

Research funding: Merck

E. Bachy

Consultant or advisory role: Roche, Incyte

Research funding: Takeda, Amgen

Other remuneration: Non‐ﬁnancial support: Roche, BeiGene, Cel-

gene, Incyte; Personal Fees: Roche, Janssen, Celgene, Novartis,

Gilead

K. Kato

Consultant or advisory role: Abbvie, AstraZeneca, Celgene, Chugai,

Janssen, Eisai, Novartis, Daiichi Sankyo

Honoraria: Takeda, MSD, Kyowa‐Kirin, Janssen, Celgene, Ono,

Mundi, Dainippon‐Sumitomo, BMS

Research funding: Chugai, Takeda, Kyowa‐Kirin, Abbvie, Eisai,

Novartis, Celgnene, Ono, Daiichi Sankyo

140

SUPPLEMENT ABSTRACTS

H. Harigae

Honoraria: BMS, Novartis, Chugai, Jansseb

Research funding: Astellas

M. José Kersten

Consultant or advisory role: Novartis, Kite/Gilead, Miltenyi Biotec,

Takeda

Honoraria: Novartis, Kite/Gilead, Roche

Educational grants: Novartis, Kite/Gilead, Roche, Celgene

C. Andreadis

Employment or leadership position: Genentech/Roche (Recipient is

an immediate family member)

Consultant or advisory role: Kite/Gilead, Karyopharm Therapeutics,

Atara Biotherapeutics, Incyte, TG Therapeutics, Epizyme

Stock ownership: Genentech/Roche (Recipient is an immediate family

member)

Research funding: Novartis, GSK, Amgen, Juno Therapeutics, Cel-

gene, Merck

Educational grants: Kite/Gilead

P. A. Riedell

Consultant or advisory role: Kite/Gilead, Celgene/BMS, MorphoSys

Takeda, Verastem, Karyopharm Therapeutics, Calibr, Bayer

Educational grants: Novartis

A. Zia

Employment or leadership position: Novartis

M. C. Morisse

Employment or leadership position: Novartis

N. H. Fowler

Consultant or advisory role: Genentech/Roche, TG Therapeutics,

Verastem, Bayer, Celgene, Novartis

Research funding: Roche, Celgene, Novartis, Gilead Sciences, TG

Therapeutics, Novartis, Abbvie, BeiGene

C. Thieblemont

Honoraria: Roche, Incyte, Novartis, Janssen, Bayer, Abbvie, Gilead

sciences, Celgene

Research funding: Roche

Educational grants: Roche, Novartis, Kite/Gilead, Janssen‐Cilag

086 |TRANSCEND CLL 004: PHASE 1 COHORT OF

LISOCABTAGENE MARALEUCEL (LISO‐CEL) COMBINED WITH

IBRUTINIB (IBR) FOR PATIENTS (PTS) WITH R/R CLL/SLL

W. G. Wierda

, K. A. Dorritie

, J. Munoz

, D. M. Stephens

S. Solomon

, H. H. Gillenwater

, L. Gong

, L. Yang

, K. Ogasawara

J. Thorpe

, T. Siddiqi

The University of Texas MD Anderson Cancer Center, Department of

Leukemia, Division of Cancer Medicine, Houston, Texas, USA,

UPMC

Hillman Cancer Center, Division of Hematology/Oncology, Pittsburgh,

Pennsylvania, USA,

Banner MD Anderson Cancer Center, Department

of Lymphoma/Myeloma, Phoenix, Arizona, USA,

Hutsman Cancer

Institute, University of Utah, Salt Lake City, Utah, USA,

Immunotherapy Program, Northside Hospital Cancer Institute, Atlanta,

Georgia, USA,

Bristol Myers Squibb, Global Clinical Development,

Seattle, Washington, USA,

Bristol Myers Squibb, Clinical Research and

Development, Seattle, Washington, USA,

Bristol Myers Squibb, Global

Biometric and Data Science, Seattle, Washington, USA,

Bristol Myers

Squibb, Clinical Pharmacology and Pharmacometrics, Princeton, New

Jersey, USA,

Bristol Myers Squibb, Immunomodulatory therapies,

Seattle, Washington, USA,

City of Hope National Medical Center,

Department of Hematology & Hematopoietic Cell Transplantation,

Duarte, California, USA

Introduction: Liso‐cel is a CD19‐directed CAR T cell product

administered at equal target doses of CD8

and CD4

CAR

cells. We report updated safety and efﬁcacy from the investiga-

tional phase 1 liso‐cel +ibr dose escalation cohort of the phase 1/

2 TRANSCEND CLL 004 study (NCT03331198) in pts with R/R

CLL/SLL.

Methods: Eligible pts with R/R CLL/SLL met ≥1 of the following:

progressed on ibr by enrollment; had high‐risk features and were

on ibr for ≥6 months (mo) with <CR; had a BTK or PLCγ2gene

mutation; had previous ibr and no contraindication to reinitiating

it. At enrollment, pts started or continued ibr 420 mg/day through

leukapheresis and for 90 days after liso‐cel infusion. Pts received

liso‐cel infusion at 50 �10

(dose level [DL]1) or 100 �10

(DL2)

CAR

T cells after 3 days of lymphodepletion with ﬂudarabine/

cyclophosphamide. Primary objectives for phase 1 were safety and

determining the recommended dose of liso‐cel when given with

ibr. Antitumor activity (ORR [CR +CR with incomplete blood

count recovery (CRi)] +PR) and cellular kinetics were exploratory

objectives.

Results: At data cutoff, 19 pts received liso‐cel (DL1, n =4; DL2, n

=15) with ibr. Median age was 61 (range, 50‒77) years, and 18

pts (95%) had high‐risk cytogenetics (del[17p], n =8; TP53 mu-

tation, n =6; complex karyotype [≥3 chromosomal aberrations], n

=8). Pts had a median of 4 (range, 1‒10) prior therapies. All pts

were R/R to prior ibr; 11 pts (58%) had disease refractory to ibr

and venetoclax. Two pts were treated as outpatients. No dose‐

limiting toxicities were observed at either DL. Most pts (n =15,

79%) experienced ibr‐related TEAEs; 7 (37%) were grade ≥3. Ibr‐

related TEAEs in 2 and 4 pts led to dose reductions and discon-

tinuations, respectively (Table). No grade 5 TEAEs occurred.

Cytokine release syndrome (CRS) was reported in 14 pts (74%),

with 1 grade 3 event; 6 (32%) reported neurological events (NEs; 3

grade ≥3). Eight pts (42%) received tocilizumab and/or cortico-

steroids to manage CRS and/or NEs. Preliminary cellular kinetics

data showed a median time to peak liso‐cel expansion of 11 days

(IQR, 10–15). Of 19 pts with ≥1‐mo follow‐up, 18 (95%) had an

objective response; 12 (63%) had a CR/CRi. One pt (5%) had

stable disease. Responses were achieved by Day 30 postinfusion,

and 16 of 18 pts (89%) have ongoing responses at ≥6 mo. Of 19

pts evaluable for MRD, 17 (89%) achieved undetectable MRD in

SUPPLEMENT ABSTRACTS

141

blood via ﬂow cytometry and 15 (79%) in bone marrow by next‐

generation sequencing (sensitivity of both, ≤10

–4

Conclusions: Preliminary data show that liso‐cel +ibr was asso-

ciated with manageable safety, including a low incidence of grade

≥3 CRS and NEs, and promising efﬁcacy in heavily pretreated pts,

who were all R/R to prior ibr, with R/R CLL/SLL. No clear differ-

ence in safety was observed between DLs, and DL2 was selected

as the dose of liso‐cel when given with ibr in the ongoing

expansion cohort.

The research was funded by: This study was funded by Juno Thera-

peutics, a Bristol‐Myers Squibb Company. All authors contributed to

and approved the abstract; writing and editorial assistance were

provided by Jeremy Henriques, PhD, of The Lockwood Group

(Stamford, CT, USA), funded by Bristol Myers Squibb.

Keywords: Chronic Lymphocytic Leukemia (CLL), Combination

Therapies, Immunotherapy

Conﬂicts of interests pertinent to the abstract

W. G. Wierda

Research funding: GSK/Novartis, Abbvie, Genentech, Pharmacyclics

LLC, Acerta Pharma Inc, Gilead Sciences, Juno Therapeutics, KITE

Pharma, Sunesis, Miragen, Oncternal Therapeutics, Cyclacel, Loxo

Oncology Inc., Janssen, Xencor

K. A. Dorritie

Consultant or advisory role: Juno/BMS, Kite‐Gilead, Genentech/

Hoffman LaRoche, Janssen, Nordic Nanovector

J. Munoz

Consultant or advisory role: Pharmacyclics, Bayer, Gilead/Kite

Pharma, Pﬁzer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Bei-

gene, Fosunkite, Innovent, Seattle Genetics

Honoraria: Kyowa and Seattle Genetics

Research funding: Bayer, Gilead/Kite Pharma, Celgene, Merck, Por-

tola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen,

Millennium

Other remuneration: Gilead/Kite Pharma, Kyowa, Bayer, Pharma-

cyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene,

Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche, AbbVie

D. M. Stephens

Consultant or advisory role: Beigene, Jannsen, Pharmacyclics, Epi-

zyme, Adaptive, TG Therapeutics, Karyopharm, Innate

Research funding: Karyopharm, Acerta, Arqule, Mingsight, Juno,

Gilead, Verastem

H. H. Gillenwater

Employment or leadership position: Bristol Myers Squibb

Stock ownership: Bristol Myers Squibb

TABLE 1Safety and Efﬁcacy

142

SUPPLEMENT ABSTRACTS

L. Gong

Employment or leadership position: Bristol Myers Squibb

Stock ownership: Bristol Myers Squibb

L. Yang

Employment or leadership position: Bristol Myers Squibb

K. Ogasawara

Employment or leadership position: Bristol Myers Squibb

Stock ownership: Bristol Myers Squibb

J. Thorpe

Employment or leadership position: Bristol Myers Squibb

Stock ownership: Bristol Myers Squibb

T. Siddiqi

Honoraria: Juno Therapeutics, Celgene, Bristol Myers Squibb, Phar-

macyclics LLC, an Abvie Company, Kite Pharma, AstaZeneca, Bei-

Gene, Janssen

Research funding: Funding to Institution: Juno Therapeutics, Celgene,

Pharmacyclics LLC, an Abvie Company, Kite Pharma, AstraZeneca,

BiGene, TG Therapeutics, Oncternal, Ascentage Pharma

087 |OUTCOME OF LARGE B‐CELL LYMPHOMA PATIENTS

FAILING CD19 TARGETED CAR‐T THERAPY

A. Kuhnl

, A. A. Kirkwood

, M. O'Reilly

, R. Sanderson

, E. Tholouli

A. Patel

, C. Besley

, S. Iyengar

, C. Jones

, A.‐L. Latif

, J. Norman

W. Osborne

, G. Collins

, A. McMillan

, K. Ardeshna

S. Chaganti

, T. Menne

King's College Hospital, Haematology, London, UK,

University College

London, CTC, London, UK,

University College London Hospital,

Haematology, London, UK,

Manchester Royal Inﬁrmary, Haematology,

Manchester, UK,

The Christie Manchester, Haematology, Manchester,

UK,

University Hospital Bristol, Haematology, Bristol, UK,

Royal

Marsden Hospital, Haematology, London, UK,

Cardiff University Hospital,

Haematology, Cardiff, UK,

Queen Elizabeth University Hospital,

Haematology, Glasgow, UK,

Freeman Hospital, Haematology,

Newcastle, UK,

Oxford University Hospitals, Haematology, Oxford, UK,

Nottingham University Hospitals, Haematology, Nottingham, UK,

University Hospitals Birmingham, Haematology, Birmingham, UK

Background: Despite high initial response rates, most patients with

relapsed/refractory (r/r) large B‐cell lymphoma receiving CD19 tar-

geted CAR‐T therapy will progress or relapse. There are limited data

available on post‐CAR‐T management and outcomes. We provide

detailed outcome analyses from a prospective national cohort of

lymphoma patients progressing after licenced CD19 CAR‐T.

Methods: We analysed consecutive patients with r/r large B‐cell

lymphoma who received axicabtagene ciloleucel or tisagenlecleucel

between Feb 2019 ‐Dec 2020 across 10 UK centres and were pri-

mary refractory or relapsed after infusion.

Results: Of 294 patients infused with CAR‐T, 153 (52%) progressed.

143 (93%) of progressions occurred within 6 months (m) of infusion,

79 (52%) after an initial response (30 CR, 49 PR). The median time to

progression was 2.4 m (IQR: 0.99 – 13.3), 3.2 m (IQR: 2.9 – 5.1) after

initial CR vs. 3.0 m (IQR: 2.4 – 3.1) after PR.

82/153 (54%) patients received further treatment: 10 radiotherapy

(RT) alone, 31 R‐bendamustine/polatuzumab vedotin (RBP), 13 R‐

lenalidomide, 13 standard chemotherapies, 6 checkpoint inhibition

(CPI), 3 CD20xCD3 bispeciﬁc antibodies, 2 BTKi, 4 other treatments.

10 patients underwent allogeneic transplant.

Patients undergoing treatment for post‐CAR‐T relapse were younger

(med. age 56y vs. 60y; p =0.03), had better ECOG performance status

pre‐infusion (0/1: 96% vs. 76%; p =0.005), and more likely to have had

transient responses to CAR‐T (61% vs. 41%; p =0.007) compared to

patients not considered for further treatment.

With a median follow‐up of 9.6 m, median OS post CAR‐T progres-

sion was 3.7 m (95% CI: 3 – 6), with 1.4 m (95% CI: 1 – 2) for patients

not receiving further treatment, and 7.8 m (95% CI: 6 – 10) for

treated patients [11.0 m for patients responding vs. 4.5 m for non‐

responders].

The overall response rate to post‐CAR‐T treatment was 39% (28/72)

and within groups of 10+patients as follows: 15/31 (48%) for RBP, 2/

13 (15%) for standard chemotherapy, and 2/11 (18%) for R‐

lenalidomide, with a median OS post progression of 10 m (95% CI:

8 – 12), 5.2 m (2 – NR) and 7.3 m (3 – NR), respectively.

18 (22%) patients achieved CR following post‐CAR‐T therapy (3 after

RT, 10 RBP, 2 CPI, 1 bispeciﬁc antibodies, 2 chemotherapy), 9 of

which underwent allogeneic transplant. Median OS after achieving

CR was 12.3 m (5 – NR). Updated response‐and survival data will be

provided at the meeting.

Discussion: This large national real‐world cohort demonstrates the

poor outcome of lymphoma patients failing CD19 CAR‐T, with almost

half of patients not given further treatment. Response to post‐CAR‐T

therapies is limited indicating an area of unmet need in those ﬁt for

further treatment and highlighting the importance of appropriate

patient counselling. Access to effective novel agents may increase the

numbers who can be bridged to allogeneic transplant and potentially

improve long‐term outcomes.

Keywords: Aggressive B‐cell non‐Hodgkin lymphoma, Cellular

therapies

Conﬂicts of interests pertinent to the abstract

A. Kuhnl

Consultant or advisory role: Kite, Novartis, Celgene

Honoraria: Kite, Novartis

Educational grants: Kite

A. A. Kirkwood

Consultant or advisory role: Kite

M. O'Reilly

Honoraria: Kite, Novartis

Educational grants: Kite, Novartis

R. Sanderson

Honoraria: Kite, Novartis

SUPPLEMENT ABSTRACTS

143

E. Tholouli

Consultant or advisory role: Kite, Novartis

Honoraria: Kite, Novartis

A. Patel

Honoraria: Kite, Novartis

C. Besley

Honoraria: Kite, Novartis

S. Iyengar

Consultant or advisory role: Kite, Takeda, Beigene

Honoraria: Kite, Takeda

Educational grants: Abbvie

A.‐L. Latif

Honoraria: Kite, Jazz, Daiichi Sankyo, Novartis, Amgen, AbbVie,

Astellas

W. Osborne

Honoraria: Roche, Takeda, Pﬁzer, Servier, Kite Gilead, MSD, Novartis,

Beigene, Astra Zeneca, Syneos, Autolus

G. Collins

Consultant or advisory role: Kite

Honoraria: Kite, Novartis

A. McMillan

Consultant or advisory role: Roche

Honoraria: Roche

Educational grants: Roche

S. Chaganti

Honoraria: Kite, Novartis

T. Menne

Honoraria: Kite, Amgen, Novartis, Pﬁzer, Celgene, Daiichi Sankyo,

Atara, Takeda, Janssen, Roche, Servier

Research funding: Janssen, Astra Zeneca, Novartis

16‐ICML SPECIAL LECTURE: LYMPHOMA TREAT-

MENT IN DEVELOPING COUNTRIES

088 |LYMPHOMA TREATMENT IN DEVELOPING COUNTRIES

A. Biondi

Found. MBBM / San Gerardo Hospital, Pediatric Clinic, Univers. Milano‐

Bicocca, Monza (Italy)

Over the last 30 years numerous pediatric oncology programs have

been established in Low Middle Income Countries (LMIC) through

international cooperation projects. Treatment of lymphomas faced

major challenges in diagnostics requirements (pathology and imaging)

and shortage of chemotherapeutic agents and of support therapy,

with need of protocols adaptation to local situations. Projects for

Burkitt Lymphoma, facilitated by the biological features of the

disease, have been quite successful since the beginning in different

geographical areas, and particularly in Africa, where this lymphoma is

endemic. These initiatives were coordinated by the International

Society of Pediatric Oncology (SIOP), the French African Group of

Pediatric Oncology (GFAOP) and other organizations.

The Center of Pediatric Hemato‐Oncology of Monza, together with

the Pediatric Oncology Department of the Istituto Tumori of Milano

(INT), the Associazione Medica per l’aiuto al Centro America (AMCA,

Bellinzona, Switzerland) and SJCRH (USA) has pioneered Pediatric

Oncology in Nicaragua and Central America, where the Pediatric

Hemato‐Oncology Association of Central America (AHOPCA) was

instituted, to develop common treatment strategies and protocols to

diagnose and treat most common childhood malignancies in the

whole area.

Hodgkin Disease (HD) was treated initially in the early 90ies in

Nicaragua and subsequently in the AHOPCA Countries with COPP ‐

COPP/ABV courses; staging was done with X‐rays and ultrasound only;

radiation therapy (RT) was not available. Results of the AHOPCA LH

1999 protocol in 216 eligible patients showed that abandonment rate

was 14%; treatment was well tolerated; EFS at 5 and 10 years was 71%

and 68% respectively. The subsequent AHOPCA LH 2004 protocol

used ABVD courses for favorable disease and OEPA COPDac courses

for the high risk group and limited RT. The 5‐year EFS and Survival in

933 patients evaluable were 72.3% and 81.3%, with abandonment

considered event or 79.9% and 87.4% when abandonment was

censored. This experience served to generate the CLEHOP LH proto-

col, which is now used in many Countries of Latin America.

Burkitt Lymphoma has been treated with a modiﬁed reduced in-

tensity NHL BFM‐90 regimen. Despite an Induction death rate of

8.8% and an abandonment rate of 6%, a 3 years EFS of 70% was

achieved in 386 eligible patients diagnosed in the period 2004 –

2016. Currently a new study is ongoing with better control of diag-

nostic accuracy including genetics.

Patients with LACL have been treated with different protocols (APO,

a Protocol designed for T‐ALL, a modiﬁed BFM protocol) with an

overall 5‐year EFS of 67%. Lymphoblastic lymphomas are generally

treated with modiﬁed ALL protocols. Although no reports on

outcome in these patients are available, it should be slightly superior

to that of ALL, for which a long term EFS close to 50% is obtained.

The disadvantage in this disease is the need of longer treatment

duration, which is associated with toxicity deaths and high rates of

abandonment.

Overall these experiences show that, despite the diagnostic and im-

aging limitations, childhood lymphomas can be treated successfully in

LMIC if there is a local commitment. The major challenges are the

accuracy of the diagnosis, availability of antineoplastic agents and

support therapy. Global medicine programs can play a key role to

improve these outcomes, in keeping with the recommendations and

commitment by the WHO too.

Keywords: Therapeutics and Clinical Trials in Lymphoma

No conﬂicts of interests pertinent to the abstract.

144

SUPPLEMENT ABSTRACTS

DOI: 10.1002/hon.2880

SUPPLEMENT ABSTRACTS

E‐POSTERS

LYMPHOMA BIOLOGY

089 |CLINICAL IMPACT OF T‐CELL RECEPTOR REPERTOIRE

DIVERSITY IN PATIENTS WITH LYMPHOMA UNDERGOING

AUTOLOGOUS STEM CELL TRANSPLANTATION

G. Ø. Jørgensen

, F. Favero

, J. Schmidt Jespersen

, M. R. Tulstrup

F. G. Rodriguez‐Gonzalez

, A. F. Nielsen

, B. Sørensen

, L. H. Ebbe-

sen

, J. Bæch

, E. K. Haastrup

, C. Nielsen

, Pär L. Josefsson

M. Thorsgaard

, T. C. El‐Galaly

, P. Brown

, J. L. Weischenfeldt

T. S. Larsen

, K. Grønbæk

, S. Husby

Rigshospitalet, Hematology, Copenhagen N, Denmark,

Finsen

laboratory, Hematology‐Oncology, Rigshospitalet, Copenhagen, Denmark,

Rigshospitalet, Dept. of Clinical Immunology, Copenhagen, Denmark,

Aarhus University Hospitalet, Clinical Immunology, Aarhus, Denmark,

Aarhus University Hospital, Clinical Immunology, Aarhus, Denmark,

Aalborg University Hospital, Clinical Immunology, Aalborg, Denmark,

Odense University Hospital, Dept. of Clinical Immunology, Copenhagen,

Denmark,

Aarhus University Hospital, Hematology, Aarhus, Denmark,

Aalborg University Hospital, Aalborg, Aalborg, Denmark,

Odense Uni-

versity Hospital, Hematology, Odense, Denmark

The adaptive immune response, and especially the role of T‐cells has

become a key focus in the treatment of lymphoma. The T‐cell re-

ceptor (TCR) is exclusive for every T‐cell clone and thus provides

unique information about the condition of the immune system. Novel

NGS sequencing has made it possible to identify hundred thousands

of T‐cell clones in a single sample, consequently termed the TCR

repertoire. Poorer diversity of the TCR repertoire has been associ-

ated with inferior outcomes in other cancers [Thommen DS et al. –

Cancer Cell 2018]. We explored how the systemic T‐cell diversity

impacted the long‐term outcomes in lymphoma patients undergoing

high‐dose chemotherapy and autologous stem cell transplantation

(ASCT).

We performed high‐throughput RNA based sequencing of the V,

D and J segment of TCR beta chain with the Illumina Immune

Repertoire NGS panel. In 288 patients with aggressive lymphoma

(predominantly B‐cell NHL), we have sequenced the circulating TCR

repertoire in the autologous harvest products used in the ASCT. All

patients were included in a nationwide Danish cohort with full long‐

term follow‐up data on survival, infections, transfusion history and

secondary cancers [Husby S et al. – Leukemia 2020]. By using the

MiXCR and Immunarch bioinformatic pipelines we analyzed the TCR

repertoire diversity, as measured by the Chao1 estimation, and used

FIGURE 1

Hematological Oncology. 2021;39(S2):145–383. wileyonlinelibrary.com/journal/hon

145

the median value in the cohort as a cut‐off for high and low TCR

repertoire diversity, respectively.

As of March 2021, analysis of 92 patients had been ﬁnalized.

Patients older than 60 years had a signiﬁcantly lower TCR repertoire

diversity compared to younger (p =0.03, Wilcoxon rank sum test).

There was no association between lymphoma subtype and TCR

repertoire diversity. In a Kaplan‐Meier survival analysis we found a

trend towards longer overall survival in patients with high TCR

repertoire diversity (Figure 1).

Detailed proﬁling of the TCR repertoire coupled with long

term follow‐up of patients undergoing ASCT may provide novel

information regarding the impact of the patient's own adaptive

immune response on treatment efﬁcacy. A dysfunctional T‐cell

repertoire can furthermore have implications for selection of pa-

tients to undergo cellular therapies (ie. ASCT or CAR T‐cell

treatment) in contrast to non‐cellular therapies (i.e. bispeciﬁc an-

tibodies, small molecule inhibitors). Full analysis of all 288 patients

and correlation with post‐transplant infections, transfusions and

secondary cancers are ongoing and will be presented at the

16‐ICML.

The research was funded by: Rigshospitalets Research Fund and

The Capital Region Denmark Research Fund.

Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-

nostic Biomarkers, Stem Cell Transplant

No conﬂicts of interest pertinent to the abstract.

090 |BASELINE CIRCULATING TUMOUR DNA AND TOTAL

METABOLIC TUMOUR VOLUME AS EARLY OUTCOME

PREDICTORS IN AGGRESSIVE B‐CELL LYMPHOMA. A REAL LIFE

PROSPECTIVE 112‐PATIENT COHORT

E. Le Goff

, P. Blanc‐Durand

, L. Roulin

, R. Loyaux

, D. L. MBoum-

bae

, E. Poullot

, C. Robe

, I. Benmaad

, G. Gricourt

, A. Aissat

C. Copie‐Bergman

, F. Lemonnier

, P. Gaulard

, E. Itti

, C. Haioun

M.‐H. Delfau Larue

Assistance Publique Hôpitaux de Paris, APHP, University Hospital Henri

Mondor, Lymphoid malignancies unit, Creteil, France,

Assistance Publique

Hôpitaux de Paris, APHP, University Hospital Henri Mondor, Nuclear

medicine, Creteil, France,

Assistance Publique Hôpitaux de Paris, APHP,

University Hospital Henri Mondor, hematobiology and Immunobiology

Department, Creteil, France,

Assistance Publique Hôpitaux de Paris, APHP,

University Hospital Henri Mondor, Pathology department, Creteil, France,

Assistance Publique Hôpitaux de Paris, APHP, University Hospital Henri

Mondor, Bioinformatics department, Creteil, France

Introduction: The addition of rituximab to CHOP chemotherapy

(R‐CHOP) has improved the outcome of patients with aggressive

B‐cell lymphoma. However, depending on their speciﬁc adverse

prognostic factors, approximately 30 to 40% have a poor outcome.

Besides the International Prognostic Index (IPI), circulating cell free

tumour DNA (CtDNA) load and baseline total metabolic tumour

volume (TMTV) have been shown to predict progression‐free survival

(PFS) and survival, mostly in retrospective studies. The aim of this

study was to evaluate the combined prognostic value of CtDNA and

TMTV at diagnostic in a prospective “real life” cohort of previously

untreated aggressive B‐cell lymphoma.

Methods: Clinical features, plasma sampling and FDG PET/CT of

consecutive patients diagnosed with aggressive B‐cell lymphoma

between 2017 and 2020 were collected in a single institution. Next

generation sequencing of the 36 Lymphopanel targeted B‐cell lym-

phoma gene was performed on CfDNA, and CtDNA load calculated

(Bohers et al., Blood Cancer J 2018). TMTV was calculated using fully

automatic segmentation of lymphoma lesions by artiﬁcial intelligence

(Blanc‐Durand et al., EJNMMI 2020). Optimal cut‐offs of CtDNA and

TMTV to predict PFS were determined by ROC and xTile analyses.

Results: We included 112 patients with aggressive B‐cell lymphoma:

87 diffuse large B‐cell lymphoma, 7 high‐grade B‐cell lymphoma, 5

primary mediastinal B‐cell lymphoma and 3 others, of whom 79 had a

paired biopsy analysis. Median age was 63 years (20‐91), 83% pa-

tients had stage III/IV disease and 54% had elevated IPI (3‐5).

Regarding Hans status, 52% were non‐germinal center (nonGC). All

patients received R‐CHOP/CHOP‐like chemotherapy, with central

nervous system prophylaxis in 49. CtDNA was detected in CfDNA in

95/112 patients (85%) with a median of 3.15 LOG haplotype equiv-

alent genome per mL (extremes 1.4‐5 LOGhEG/mL). TMTV was

available in 102 patients with a median of 501 mL (extremes 4‐5151

mL). With a median follow‐up of 14 months, a signiﬁcantly lower 1‐

year PFS was observed in patients with a high (>3.8 LOGhEG/mL)

CtDNA load (45% vs. 81%, P =0.002, HR =2.6 [1.16‐7.28]) and with

a high (>200 mL) TMTV (64% vs. 97%, P =0.01, HR =3.56 [1.64‐

7.73]). Patients with both high CtDNA and TMTV values (high‐high)

had a lower 1‐year PFS than those with discrepant or both low values

(low‐low): 1‐year PFS estimates were 45% vs. 75% vs. 97%, respec-

tively (P =0.001, Figure 1). In multivariate Cox analysis including

146

SUPPLEMENT ABSTRACTS

Hans status, IPI, CtDNA and TMTV, only an elevated IPI (P =0.02)

and high CtDNA load (P =0.04) remained signiﬁcant.

Conclusion: Despite a limited follow‐up, this institutional study

conducted in a large cohort of patients with aggressive B‐cell lym-

phoma treated in real life, emphasizes that high CtDNA load and high

TMTV are strong predictors of poor outcome. These characteristics

at baseline could help tailoring therapy in these patients.

Keywords: Diagnostic and Prognostic Biomarkers, PET‐CT, Liquid

biopsy

No conﬂicts of interest pertinent to the abstract.

091 |CIRCULATING TUMOR DNA LOAD AND TOTAL

METABOLIC TUMOR VOLUME IN DIFFUSE LARGE B CELL

LYMPHOMA (DLBCL) PATIENTS TREATED BY R‐CHOP – FROM

REMARC, A LYSA STUDY

E. Bohers

, M. Delfau‐Larue

, L. Vercellino

, A. Cottereau

, M.

Viennot

, P. Viailly

, G. Salles

, H. Tilly

, G. Damaj

, C. Haioun

, V.

Ribrag

, F. Morschhauser

, R. Casasnovas

, E. Nicolas‐Virelizier

P. Feugier

, R. Bouabdallah

, G. Cartron

, L. Renaud

, L. Chart-

ier

, C. Portugues

, M. Meignan

, F. Jardin

, C. Thieblemont

Team Genetics and Biomarkers in Lymphoma and Solid Tumors, INSERM

U1245, Normandy University, Rouen, France,

Hematobiology and

Immunobiology Department, INSERM U955 Eq9, APHP, University

Hospital Henri Mondor, Créteil, France,

Department of Nuclear Medicine,

APHP, Saint‐Louis Hospital, Paris, France,

Department of Nuclear Medi-

cine, APHP, Cochin, Paris, France,

Memorial Sloan Kettering Cancer Cen-

ter, Lymphoma Department, New York, New York, USA,

Department of

Hematology, Henri Becquerel Center, Rouen, France,

Department of He-

matology, Caen University Hospital, Caen, France,

Department of Hema-

tology, Henri Mondor University Hospital, Créteil, France,

Department of

Hematology, Gustave Roussy Institute, Villejuif, France,

Department of

Hematology, Lille University Hospital, Lille, France,

Department of He-

matology, Dijon University Hospital, Dijon, France,

Department of He-

matology, Leon Berard Center, Lyon, France,

Department of Hematology,

Nancy university Hospital, Vandoeuvre‐les‐Nancy, France,

Department

of Hematology, Paoli Calmette Institute, Marseille, France,

Department of

Hematology, Montpellier University Hospital, Montpellier, France,

Department of Hematology, Lille University Hospital, Lille, France,

LYSARC, Lyon Hospital, Pierre‐Benite, France,

Department of Nuclear

Medicine, APHP, University Hospital Henri Mondor, Creteil, France,

Department of Hematology, APHP, Saint‐Louis Hospital, Paris, France

Background: Circulating tumor DNA (ctDNA) quantiﬁcation has been

shown to predict therapeutic beneﬁt in patients (pts) with DLBCL. We

recently investigated the prognostic impact of total metabolic tumor

volume (TMTV) in DLBCL pts responder to R‐CHOP in the REMARC

study. In the present ancillary study, we wish to analyze the potential

correlation of ctDNA with the outcome and relate these results to

functional imaging by PET/CT (TMTV). We also aim to correlate the

circulating tumor DNA load with the new score TMTV plus ECOG PS.

Patients and Methods: 794 pts were included in the study either at

diagnosis (n =446) or at the end of R‐CHOP (n =347). At the end of

R‐CHOP, 650 pts achieved a complete response and were random-

ized to receive 2 years of lenalidomide or placebo. Tumoral cfDNA

measurements were performed using a dedicated 36 genes panel

with the QiaSeq® technology. CtDNA concentrations were

expressed in haploid genome equivalents per mL of plasma (hGE/mL)

and calculated by multiplying the mean variant allele frequency (VAF)

by the concentration of total cfDNA (Bohers et al. Blood Cancer J

2018).The optimal ctDNA cut‐offs for PFS and OS were determined

by X‐tile analyses and conﬁrmed by a training validation method.

Results: A total of 240 pts were analyzed, including 62 non‐responder

and non‐randomized pts (NR‐NRP) and 173 responder and random-

ized pts (REMARC pts). 5 pts had no interpretable ctDNA analysis and

were excluded.

Among the 235 NR‐NRP/REMARC cohort, a ctDNA >3.74 was

present in 14% of pts and was predictive for PFS (HR =1.68, 95%CI

1.02–2.76, p =0.0397) and OS (HR =2.15, 95%CI 1.28‐3.61,

p=0.0031). The 3y‐PFS for pts with a ctDNA >3.74 was 47.3% (95%

CI: 30%‐63%) vs 71.5% (95% CI: 65%‐77%) for pts with a ctDNA ≤

3.74. The 3y‐OS for pts with a ctDNA >3.74 was 56.4% (95%CI:

38%‐71%) vs 81.8% (95% CI: 76%‐87%) for pts with a ctDNA ≤3.74.

Among the 173 R‐CHOP responder patients (REMARC cohort),

the 12 months‐relapse free survival since last cycle of R‐CHOP for pts

with a ctDNA >3.74 at diagnosis was 61.1% (95%CI: 35%‐79%) vs

88.7% (95%CI: 82%‐93%) for pts with a ctDNA ≤3.74 (p =0.009).

However, a ctDNA >3.74 was not predictive either for PFS (HR =1.64,

95%CI: 0.84‐3.21, p =0.14) nor for OS (HR =1.91 95%CI: 0.93‐3.89, p

=0.07). Among the 100 pts with ctDNA and TMTV available, median

log ctDNA was found signiﬁcantly higher in TMTV >220 (n =58) vs

TMTV <220 (p =0.002). However, no signiﬁcant impact of ctDNA

(threshold 3.4) and TMTV(threshold 220) was observed on PFS and OS.

Conclusion: Using a routinely targeted sequencing panel for ctDNA

measurement, we conﬁrmed the prognostic value of ctDNA con-

centration to predict outcome in DLBCL patients. For patients

responding to R‐CHOP, high ctDNA level was signiﬁcantly associated

with high TMTV and early relapse.

The research was funded by: BMS

Keywords: Diagnostic and Prognostic Biomarkers, Aggressive B‐cell

non‐Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

092 |HIGH RISK AGGRESSIVE B‐CELL LYMPHOMA ON THE

LIQUID BIOPSY

L. Meriranta

, A. Alkodsi

, A. Pasanen

, M. Lepistö

, Y. N. Blaker

J. Jørgensen

, P. Mapar

, M. Björkholm

, M. Jerkeman

, H. Holte

E. Pitkänen

, P. Ellonen

, S. Leppä

University of Helsinki and Helsinki University Hospital Comprehensive

Cancer Centre, Department of Oncology and Applied Tumor Genomics

Research Program, Helsinki, Finland,

University of Helsinki, Institute for

SUPPLEMENT ABSTRACTS

147

Molecular Medicine Finland, Helsinki, Finland,

Oslo University Hospital,

Department of Oncology, Oslo, Norway,

Aarhus University Hospital,

Department of Hematology, Aarhus, Denmark,

University of Helsinki,

Institute for Molecular Medicine Finland, HiLIFE & Applied Tumor Geno-

mics Research Program, Helsinki, Finland,

Karoliska Institutet, Depart-

ment of Medicine, Stockholm, Sweden,

Lund University, Department of

Oncology, Lund, Sweden,

University of Helsinki, Institute for Molecular

Medicine Finland, Helsinki, Finland

Introduction: Inadequate molecular recognition of high‐risk diffuse

large B‐cell lymphoma (DLBCL) hampers the discovery of novel

treatments for the patients with poor outcome. We aimed to delin-

eate molecular determinants of outcome within the ctDNA of the

patients with aggressive B‐cell lymphoma.

Methods: We applied whole‐genome and targeted unique molecular

identiﬁer corrected sequencing to serially sampled plasma cell‐free

DNA of 101 patients less than 65 years with high‐risk (aaIPI 2‐3

and/or site‐speciﬁc risk factors for central nervous system (CNS)

progression) aggressive B‐cell lymphoma (Figure 1A). The patients

were treated in a Nordic Lymphoma Group (NLG) phase II trial with

dose‐dense immunochemotherapy and early CNS prophylaxis (Leppä

et al., Blood Advances 4(9):1906‐1915, 2020).

Results: We found that the patients with high pretreatment ctDNA

burden (log hGE/ml) were at high risk of relapse and early death from

lymphoma (Figure B‐C). In contrast, non‐lymphoma related treat-

ment failures were mainly seen in the patients with low to moderate

ctDNA levels. High ctDNA burden overcame the conventional mea-

sures of high tumor burden and other high‐risk features including

double‐hit lymphomas.

Chemorefractory disease exhibited diverging ctDNA kinetics

during therapy, whereas late molecular responses, and end‐of‐

treatment negativity for minimal residual disease characterized

cured patients (Figure 1D). As a proof‐of‐concept, we show that

advanced ctDNA tools based on hypermutation patterns and frag-

mentation pattern disparities can complement prediction of pro-

gression at the end of therapy, and provide tools to clinical

challenges, including false residual PET positivity.

Lastly, we analyzed the potential of non‐invasive ctDNA inter-

rogation for somatic drivers, hypermutation signatures and variant

haplotypes to offer novel translational information for diagnostics

and understanding of treatment‐refractoriness in patients with

aggressive B‐cell lymphoma. Genomic dissection of pretreatment

ctDNA revealed a strong association between TP53‐loss and high

ctDNA burden – a duo that in the context of high‐risk biology

rendered lymphomas refractory to frontline treatment. In contrast,

subclonal MYC lesions that were not detectable at diagnosis were

positively selected at late relapses following complete responses to

the initial therapy. We further identiﬁed that the limitations of tissue

biopsies can culminate in diagnosis‐changing discoveries in plasma

ctDNA, including progression‐driving transformation to high‐grade

B‐cell lymphoma.

FIGURE 1 Circulating tumor DNA in the NGL phaseII trial. A) Sample collection. B) Pretreatment ctDNA burden and response to

theraphy. C‐D) Survival according to (C) pretreatment ctDNA burden, and (D) ctDNA‐based detection of molecular residual disease (MRD) in

post‐treatment sample

148

SUPPLEMENT ABSTRACTS

Conclusions: Our integrative approach with prospectively collected

serial plasma samples reveals that quantitative, mutational and

fragmentation pattern features of ctDNA can be utilized as novel

diagnostic and prognostic tools in aggressive B‐cell lymphomas.

EA ‐previously submitted to EHA 2021.

The research was funded by: Academy of Finland, Finnish Cancer Or-

ganizations, Southern Finland National Cancer Center, Sigrid Juselius

Foundation, Helsinki University Hospital, Nordic Cancer Union

Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-

nostic Biomarkers, Aggressive B‐cell non‐Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

093 |IMMUNE AND VIRUS‐SPECIFIC RESPONSES IN

PARTICIPANTS WITH PRIMARY EFFUSION LYMPHOMA

RECEIVING LENALIDOMIDE, DOSE‐ADJUSTED EPOCH, AND

RITUXIMAB (EPOCH‐R

)

K. Lurain

, R. Roshan

, R. Ramaswami

, R. Mangusan

, A. Widell

I. Ekwede

, J. M. Ziegelbauer

, T. S. Uldrick

, D. Whitby

R. Yarchoan

, L. T. Krug

National Cancer Institute, HIV and AIDS Malignancy Branch, Bethesda,

Maryland, USA,

Frederick National Laboratory for Cancer Research, Viral

Oncology Section, AIDS and Cancer Virus Program, Leidos‐Biomedical,

Frederick, Maryland, USA,

Fred Hutchinson Cancer Research Center,

Division of Global Oncology, Department of Medicine, Seattle, Washing-

ton, USA

Background: Primary effusion lymphoma (PEL) is an aggressive HIV‐

associated B cell lymphoma caused by Kaposi sarcoma herpesvirus

(KSHV, human herpesvirus 8). We presented safety data of a pro-

spective phase 1 of dose‐adjusted etoposide, vincristine, doxorubicin,

cyclophosphamide, and prednisone with rituximab and lenalidomide

(EPOCH‐R

) in untreated PEL at the ASH Annual Meeting 2020

(Abstract 2105). 6 HIV

cisgender men received antiretroviral ther-

apy, lenalidomide 25 mg days 1‐10, and EPOCH‐R for 6 cycles. 3

participants (pts) had complete responses (responders); 3 had pro-

gressive/stable disease (non‐responders) at end‐of‐treatment (EOT).

Methods: We performed ﬂow cytometry evaluating T cell subsets,

monocytes (monos), and neutrophils at baseline (BL), post‐cycle 1

(C1), post‐cycle 4 (C4), EOT, and 1‐year post‐EOT (YR1). KSHV and

CMV/EBV/inﬂuenza‐speciﬁc T cell responses were measured using

an interferon‐gamma (IFN‐g) ELISPOT assay at BL, EOT, and YR1.

We determined breadth of virus‐speciﬁc responses by the number of

KSHV open reading frames (ORFs) eliciting IFN‐g responses and in-

tensity of responses by mean spot forming units (SFUs) per 10

PBMCs. Comparisons were evaluated by Wilcoxon rank sum and

Spearman correlation.

Results: At BL, responders had a higher percentage of inﬂammatory

tissue factor (TF)

CD14

monos compared with non‐responders

(median [med] 30% vs 10%, p =0.049), higher percentage of PD‐1

SUPPLEMENT ABSTRACTS

149

CD4

effector memory (CD27

‐

CD45RO

) T (TEM) cells (med 90% vs

71%, p =0.049), and lower percentage of CD38

CD8

TEM cells

(med 75% vs 96%; p =0.049). Responders had a decrease in TF

CD14

monos from BL to C1 and C4 (p =0.049 and 0.049) and

decrease in PD‐L1

CD14

monos from BL to C1 (p =0.049)

compared to non‐responders. PD‐L1 expression on monos and neu-

trophils was strongly correlated (r =0.74), and TF and PD‐L1

expression on monos was correlated (r =0.45) when analyzing

EOT and YR1 changes from BL. KSHV ORF reactivity was variable

across pts with no differences in breadth or intensity between

response groups. KSHV‐speciﬁc responses strongly correlated with

EOT and YR1 changes from BL in CD8 counts (r =0.86) and nega-

tively correlated with EOT and YR1 changes from BL in PD‐L1

expression on monos and neutrophils (r =‐0.57 and ‐0.69).

Conclusions: TF

and PD‐L1

expression on monos and PD‐1

expression on CD4

TEM cells may predict treatment outcomes in

pts with PEL receiving EPOCH‐R

. More data are needed to under-

stand how virus‐speciﬁc responses affect outcomes. Immune re-

sponses will be further evaluated in an ongoing phase 2.

The research was funded by: the Intramural Research Program of the

NIH, National Cancer Institute and by US federal funds from the

National Cancer Institute, National Institutes of Health, under Con-

tract No.HHSN261200800001E.

Keywords: Diagnostic and Prognostic Biomarkers, Aggressive B‐cell

non‐Hodgkin lymphoma, Combination Therapies

Conﬂicts of interests pertinent to the abstract

K. Lurain

Research funding: BMS‐Celgene through CRADA with the NCI

R. Ramaswami

Research funding: BMS‐Celgene through CRADA with the NCI

T. S. Uldrick

Research funding: BMS‐Celgene through CRADA with the NCI

Other remuneration: Co‐inventor on US Patent 10,001,483

D. Whitby

Other remuneration: Co‐inventor on US Patent 10,001,483

R. Yarchoan

Research funding: BMS‐Celgene through CRADA with NCI

Other remuneration: Co‐inventor on US Patent 10,001,483

094 |CLINICAL RESPONSES TO ODRONEXTAMAB

(REGN1979): CORRELATION WITH LOSS OF CD20 EXPRESSION

AS A POTENTIAL MECHANISM OF RESISTANCE AND BASELINE

BIOMARKERS OF TUMOR T CELLS

J. Brouwer‐Visser

, N. Fiaschi

, R. P. Deering

, A. Dhanik

, K. J.

Cygan

, W. Zhang

, S. Jeong

, S. Pourpe

, L. Boucher

, S. Hamon

, M.

S. Topp

, R. Bannerji

, J. Duell

, R. H. Advani

, D. M. Flink

, A.

Chaudhry

, A. Sirulnik

, I. Lowy

, A. J. Murphy

, D. M. Weinreich

G. D. Yancopoulos

, G. Thurston

, S. R. Ambati

, V. Jankovic

Regeneron Pharmaceuticals, Inc, Precision Medicine, Tarrytown, New

York, USA,

Regeneron Pharmaceuticals, Inc, Oncology and Angiogenesis,

Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc, VI Next,

Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc, Molecular

Proﬁling and Data Science, Tarrytown, New York, USA,

Universitätsklinikum Würzburg, Department of Internal Medicine 2,

Würzburg, Germany,

Rutgers Cancer Institute of New Jersey, Division of

Blood Disorders, New Brunswick, New Jersey, USA,

Stanford University,

Department of Medicine, Stanford, California, USA,

Regeneron

Pharmaceuticals, Inc, Global Development, Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc, Hematology, Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc, Global Clinical Development,

Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc, Translation

Science and Oncology, Tarrytown, New York, USA,

Regeneron

Pharmaceuticals, Inc, Research, Tarrytown, New York, USA,

Regeneron

Pharmaceuticals, Inc, Head of Global Clinical Development, Tarrytown,

New York, USA,

Regeneron Pharmaceuticals, Inc, Chief Scientiﬁc Ofﬁcer,

Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc, Oncology

Research, Tarrytown, New York, USA,

Regeneron Pharmaceuticals, Inc,

Clinical Sciences Hematology, Tarrytown, New York, USA

Introduction: Odronextamab (REGN1979) is a fully human CD20 �

CD3 bispeciﬁc antibody being evaluated in patients (pts) with

relapsed/refractory B‐cell non‐Hodgkin lymphoma (R/R B‐NHL). At

selected doses, odronextamab has demonstrated durable response

rates in pts with R/R follicular lymphoma (FL: ∼90%), and R/R diffuse

large B‐cell lymphoma (DLBCL: ∼60%). Tumor biopsies from a Phase

1 study (NCT02290951) were analyzed to investigate the association

of B‐and T‐cell biomarkers with initial clinical response and with

instances of subsequent progression.

Methods: Tumor biopsies were collected at baseline, on treatment,

and at disease progression (PD) (N =30; DLBCL n =19; FL n =9;

mantle cell lymphoma n =2), and from reference B‐NHL cases (N =

47 at diagnosis; N =39 R/R). B‐cell markers were analyzed by semi‐

quantitative chromogenic CD20 immunohistochemistry (IHC) and

multiplex immunoﬂuorescence. Tumor‐inﬁltrating immune cells were

analyzed by multiplex immunoﬂuorescence. Quantitative image

analysis was performed. Single‐cell sequencing and ﬂow cytometry

were performed in one patient with FL with PD 6 months post‐

therapy.

Results: Most baseline R/R B‐NHL biopsies (29/30, 96.7%) were

CD20+, whereas CD19 expression was variable. Relative baseline

IHC CD20 levels did not predict odronextamab response and CD20

intensity was similar in pts with FL or DLBCL. Moreover, 2/4 pts with

<100% CD20+B cells achieved durable responses. In 9/11 cases of

PD on treatment with paired biopsy samples available (DLBCL n =6;

FL n =3), loss of CD20 expression was observed; mutations ac-

counting for loss of CD20 expression were deﬁned in three of these

pts (DLBCL n =2; FL n =1). These mutations were identiﬁed after

PD, where pts had received an active odronextamab dose and

experienced responses before progressing at weeks 24–25.

Baseline T‐cell inﬁltration was higher in pts with FL vs DLBCL in

both the reference and study populations. Pts with DLBCL also had a

150

SUPPLEMENT ABSTRACTS

higher median density of T‐cell inﬁltration in odronextamab re-

sponders vs non‐responders.

Single‐cell analysis of a fresh lymph node sample from a case of

PD, occurring after a complete response to odronextamab, revealed a

near‐complete loss of CD20 protein expression on B cells, while

maintaining CD19 and CD20 mRNA expression.

Conclusions: CD20 expression is almost ubiquitous in R/R B‐NHL

biopsy samples, whereas CD19 expression is variable. Durable

odronextamab responses were observed independently of variable

CD20 levels by IHC; therefore, baseline CD20 IHC expression is not

supported as a pt selection biomarker. Loss of CD20 cell surface

expression, caused by deﬁned mutations leading to lack of protein

expression, occurred in several cases of relapsed disease, suggesting

target‐dependent escape. We also observed an association between

T‐cell inﬁltration at baseline and odronextamab response in DLBCL;

additional studies are ongoing.

The research was funded by: Regeneron Pharmaceuticals, Inc.

Keywords: Immunotherapy

Conﬂicts of interests pertinent to the abstract

J. Brouwer‐Visser

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

N. Fiaschi

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

R. P. Deering

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

A. Dhanik

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

K. J. Cygan

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

W. Zhang

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

S. Jeong

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

S. Pourpe

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

L. Boucher

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

S. Hamon

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

M. S. Topp

Consultant or advisory role: Amgen, KITE, Novartis, Regeneron, Roche

Research funding: Amgen, Boehringer Ingelheim, KITE, Regeneron,

Roche

R. Bannerji

Employment or leadership position: Sanoﬁ‐Pasteur (Spouse)

Consultant or advisory role: AbbVie, Celgene, Regeneron

Research funding: AbbVie, Regeneron Pharmaceuticals, Roche‐

Genentech and Pharmacyclics LLC, an AbbVie Company

J. Duell

Research funding: Morphosys

R. H. Advani

Consultant or advisory role: Astra Zeneca, Bayer Healthcare Phar-

maceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, Kite-

Pharma, Kyowa, Portola Pharmaceuticals, Sanoﬁ, Seattle Genetics,

Takeda

Other remuneration: INSTITUTIONAL RESEARCH SUPPORT: Cel-

gene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical,

Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics

D. M. Flink

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

A. Chaudhry

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

A. Sirulnik

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

I. Lowy

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

A. J. Murphy

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

D. M. Weinreich

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

G. D. Yancopoulos

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

G. Thurston

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

SUPPLEMENT ABSTRACTS

151

S. R. Ambati

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

V. Jankovic

Employment or leadership position: Regeneron Pharmaceuticals, Inc

Stock ownership: Regeneron Pharmaceuticals, Inc

095 |HIGHLY MULTIPLEX TISSUE IMAGING OF DLBCL

IDENTIFIES NOVEL PATHOLOGICAL FEATURES PREDICTIVE OF

OVERALL SURVIVAL

D. R. McNally

, H. Ravichandran

, W. Tam

, C. Steidl

, D. W. Scott

A. Melnick

, O. Elemento

Weill Cornell Medicine, Physiology and Biophysics, New York, New York,

USA,

Weill Cornell Medicine, Englander Institute for Precision Medicine,

New York, New York, USA,

Weill Cornell Medicine, Pathology and

Laboratory Medicine, New York, New York, USA,

BC Cancer, Centre for

Lymphoid Cancer, Vancouver, Canada,

Weill Cornell Medicine, Medicine,

New York, New York, USA

Introduction: Diffuse large B‐cell lymphoma (DLBCL) is the most

common subtype of non‐Hodgkin lymphoma and is known to be a

highly heterogenous disease. Several recent studies have identiﬁed

subtypes based on prominent genetic patterns; however, efforts to

identify relationships between these genetic groups and the patho-

physiology of the disease remain limited. Characterization of tumor

phenotypes and their microenvironments alongside genomic alter-

ations will provide much needed context and may assist in identifying

novel therapeutic targets or improvements in patient stratiﬁcation

without the use of genetic testing.

Methods: We used imaging mass cytometry (Hyperion imaging sys-

tem) to simultaneously quantify 2 sets of 37 target antigens across

serial sections of tumor tissues. A total of 64 unique antigens were

quantiﬁed across 1132 high‐dimensional images from 370 tumors.

Detailed clinical information including treatment outcome after R‐

CHOP immunotherapy is available for 303 patients, with informa-

tion on common genetic alterations available for 338. Existing

frameworks for cell segmentation (DeepCell) and single‐cell clus-

tering (Seurat) were used to process and identify major cell types and

functional states in an unsupervised manner. Additionally, a propor-

tional hazards regression model incorporating normalized quantiﬁ-

cation of all tumor biomarkers was used to identify relationships to

treatment outcome and survival.

Results: Clustering of patients solely by cellular composition resulted

in 8 distinct groups. Notably, a cluster depleted of tumor inﬁltrating

immune cells with high tumoral BCL2 expression was found to be

signiﬁcantly enriched for MYC and BCL2 double‐hit status (q =1.27 �

‐6

). In line with previous work, the double‐hit associated cluster

had signiﬁcantly worse overall survival (HR =2.45; p <0.0001).

Additionally, a subset deﬁned by canonical ABC features, a high

proliferation score, and a prominent anti‐inﬂammatory immune

response was found to have poor OS (HR =1.45; p <0.05). As

previously reported, high CD20 expression was found to be signiﬁ-

cantly associated with superior OS (HR =0.57; p <0.05). Tumor

expression of other markers including BCL2 (HR =1.3; p <0.05),

phospho‐histone H3 s28 (HR =1.4; p <0.005), and T‐bet (HR =1.4,

p<0.05) were found to be associated with inferior outcomes.

Conclusions: Advances in multiplex tissue imaging have provided a

framework to rapidly improve our understanding of tumor patho-

physiology and relationships with genomic alterations. Expanded

screening of antigen targets will likely yield novel biomarkers that

can then be translated to conventional IHC methods for improved

patient stratiﬁcation.

The research was funded by: NIH grants UL1TR002384,

R01CA194547, LLSSCOR grants 180078‐02, 7021‐20

Keywords: Bioinformatics; Computational and Systems Biology, Tu-

mor Biology and Heterogeneity, Aggressive B‐cell non‐Hodgkin

lymphoma

Conﬂicts of interests pertinent to the abstract

A. Melnick

Consultant or advisory role: Epizyme, Constellation, KDAC Pharma,

BMS and ExoTherapeutics

Research funding: Janssen Pharmaceuticals, Sanoﬁ and Daiichi Sankyo

O. Elemento

Consultant or advisory role: Freenome, Owkin, Volastra Therapeutics

and One Three Biotech

Research funding: Janssen, Johnson and Johnson, Volastra Thera-

peutics, AstraZeneca and Eli Lilly

096 |DIGITAL SPATIAL PROFILING OF DIFFUSE LARGE B‐CELL

LYMPHOMAS REVEALS STING AS AN IMMUNE‐RELATED

DETERMINANT OF SURVIVAL AFTER R‐CHOP THERAPY

M. M. Hoppe

, S. Fan

, P. Jaynes

, Y. Peng

, X. Liu

, S. De Mel

, L.

Poon

, E. Chan

, J. Lee

, Y. L. Chee

, C. K. Ong

, T. Tang

, S. T. Lim

W. J. Chng

, N. F. Grigoropoulos

, A. VanSchoiack

, G. Bertolazzi

Siok‐B. Ng

, C. Tripodo

, A. D. Jeyasekharan

National University of Singapore, Cancer Science Institute of Singapore,

Singapore, Singapore,

National University of Singapore, Department of

Pathology, Yong Loo Lin School of Medicine, Singapore, Singapore,

National University Health System, Department of Haematology‐

Oncology, Singapore, Singapore,

National Cancer Centre Singapore, Di-

vision of Cellular and Molecular Research, Singapore, Singapore,

National

Cancer Centre Singapore, Division of Medical Oncology, Singapore,

Singapore,

Singapore General Hospital, Department of Haematology,

Singapore, Singapore,

NanoString Technologies Inc, Seattle, USA,

Uni-

versity of Palermo, Tumor Immunology Unit, Palermo, Italy

Background: Alterations in the immune inﬁltrate of Diffuse Large B‐

Cell Lymphoma (DLBCL) are known to inﬂuence survival. However,

the relative prognostic importance of different immune components

152

SUPPLEMENT ABSTRACTS

is not clear. Digital spatial proﬁling (DSP) enables highly multiplexed

protein‐based measurement of immune markers in a single tissue

section. Here, we applied DSP to evaluate the prognostic signiﬁcance

of immune markers in R‐CHOP treated DLBCL.

Methods: We evaluated a custom NanoString immune panel in a

cohort of R‐CHOP treated DLBCL from the National University Hos-

pital Singapore (n=86) using DSP. Quantitative marker expression

values of 29 immune features were correlated with clinicopathological

features and with survival outcomes. Fluorescence‐based quantitative

immunohistochemistry (fIHC) was applied to an independent DLBCL

cohort (MDA, n=36) to validate the prognostic relevance of STING.

We also analysed mRNA data sets from the following patient cohorts:

GSE117556 (R‐CHOP, n=469/RB‐CHOP, n=459), GSE10846 (R‐

CHOP, n=233/CHOP, n=181), GSE32918 (R‐CHOP, n=141),

GSE98588 (R‐CHOP, n=101) and GSE23501 (R‐CHOP, n=67).

Results: In a multivariate cox proportional hazards model analysing

DSP data, high levels of the monocytic/macrophagic marker CD163

were associated with poor progression free survival (PFS) and overall

survival (OS) (HR progression 3.8, p=0.008; HR death 5.4, p=0.010)

while high expression of the inﬂammatory mediator STING was

associated with better PFS and OS (HR progression 0.33, p=0.020;

HR death 0.17, p=0.007). Given the role of STING in mediating

immune activation after genotoxic chemotherapy, we further evalu-

ated the clinical relevance of pre‐treatment STING expression.

Quantitative fIHC of STING associated with improved survival in an

independent cohort (n =36, MDA). Furthermore, high expression of

STING (TMEM173) correlated with favourable prognosis across

multiple gene expression datasets: GSE117556, R‐CHOP, HR death

0.58, p=0.016; GSE117556, RB‐CHOP, HR death 0.34, p=0.0001;

GSE10846, CHOP, HR death 0.46, p<0.0001; GSE98588, R‐CHOP,

HR death 0.40, p=0.019. Consistently, DLBCL cell lines activated

immune signalling pathways when treated with chemotherapy in vi-

tro, which suggested that STING levels could positively affect prog-

nosis through inﬂammatory priming. In this setting, low STING

expression could be reminiscent of an immunologically cold dark

zone microenvironment imprint in DLBCL, being listed among genes

that we found transcriptionally induced in the dark‐zone to light‐

zone transition in reactive lymphoid follicles in situ.

Conclusions: High expression of STING confers good prognosis in

DLBCL, suggesting that STING signalling is important for chemo-

therapy induced immune clearance. STING agonists may thus have a

potential application alongside chemotherapeutic approaches in

DLBCL.

The research was funded by: SBN and ADJ are supported by the

Singapore Ministry of Health's National Medical Research Council

Transition Awards (CSAINV17nov016 and NMRC/TA/0020/2013 and

NMRC/TA/0052/2016). Work in ADJ's laboratory is funded by the

Cancer Science Institute of Singapore, National University of

Singapore through the National Research Foundation Singapore and

the Singapore Ministry of Education under its Research Centres of

Excellence initiative. This research is also supported by Singapore

Ministry of Health's National Medical Research Council under its

Singapore IYMPHoma translatiONal studY (SYMPHONY)

(OFLCG18May‐0028).

Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-

nostic Biomarkers, Aggressive B‐cell non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

A. VanSchoiack

Employment or leadership position: NanoString Technologies Inc

A. D. Jeyasekharan

Consultant or advisory role: Turbine Ltd, AstraZeneca, Janssen and

MSD

Research funding: Janssen and AstraZeneca

Educational grants: Perkin Elmer

097 |MYC, BCL2 AND BCL6 COEXPRESSION PATTERNS AT

SINGLE‐CELL RESOLUTION RE‐DEFINE DOUBLE EXPRESSOR

LYMPHOMAS

M. M. Hoppe

, P. Jaynes

, S. Fan

, Y. Peng

, P. M. Hoang

, X. Liu

, S.

De Mel

, L. Poon

, E. Chan

, J. Lee

, Y. L. Chee

, C. K. Ong

, T. Tang

S. T. Lim

, N. F. Grigoropoulos

, S.‐Y. Tan

, S. S.‐S. Hue

, S.‐T. Chang

S.‐S. Chuang

, S. Li

, J. D. Khoury

, H. Choi

, P. Farinha

, A.

Mottok

, D. W. Scott

, Wee‐J. Chng

, S.‐B. Ng

, C. Tripodo

, A. D.

Jeyasekharan

National University of Singapore, Cancer Science Institute of Singapore,

Singapore, Singapore,

National University of Singapore, Department

of Pathology, Yong Loo Lin School of Medicine, Singapore, Singapore,

National University Health System, Department of Haematology‐

Oncology, Singapore, Singapore,

National Cancer Centre Singapore,

Division of Cellular and Molecular Research, Singapore, Singapore,

National Cancer Centre Singapore, Division of Medical Oncology,

Singapore , Singapore,

Singapore General Hospital, Department of

Haematology, Singapore , Singapore,

Chi‐Mei Medical Center, Depart-

ment of Pathology, Tainan, Taiwan,

The University of Texas MD

Anderson Cancer Center, Department of Hematopathology, Division

of Pathology and Laboratory Medicine, Houston, USA,

National

University of Singapore, Department of Medicine, Yong Loo Lin School of

Medicine, Singapore, Singapore,

BC Cancer Research Centre, Depart-

ment of Lymphoid Cancer Research, Vancouver, Canada,

University

Medical Center and University of Ulm, Institute of Human Genetics,

Ulm, Germany,

University of Palermo, Tumor Immunology Unit,

Palermo, Italy

Introduction: ‘Double Expressor Lymphomas’ (DEL) refer to Diffuse

Large B‐Cell Lymphomas (DLBCL) which are positive for MYC and

BCL2 by immunohistochemistry (IHC); and have poorer outcomes on

standard R‐CHOP therapy. BCL6 expression in these tumors partly

negates this prognostic effect. However, in routine IHC, these on-

cogenes are evaluated independently without probing their co‐

expression at the single‐cell level. It is therefore not known if DELs

are tumours that contain distinct MYC, BCL2 and/or BCL6

SUPPLEMENT ABSTRACTS

153

expressing clones, or if there are patterns of co‐expression under-

lying their prognostic signﬁcance.

Methods: We used multiplexed ﬂuorescence‐based quantitative

IHC (qIHC) to study oncogene co‐expression at single‐cell resolution

in four independent DLBCL cohorts: NUH (n=152), CMMC (n=

150), SGH (n=67), MDA (n=40). Mathematically modelled analyses

were performed to validate ﬁndings in gene expression cohorts

GSE10846(n =420), GSE31312(n =498), GSE32918 (n =140),

GSE117556(n =928) and a cohort with curated IHC scores; BCC (n =

316).

Results: In non‐malignant lymphoid tissues we observed spatially

ordered patterns of MYC, BCL2 and BCL6 co‐expression, charac-

terised by mutually exclusive patterns of BCL2 and BCL6 expression

in the non‐germinal centre and germinal centre compartments

respectively. In contrast, we noted grossly disordered patterns of

MYC(M), BCL2(2), and BCL6(6) co‐expression in DLBCL. Tumors

showed unique repertoires of cells displaying eight possible permu-

tations of co‐expression: M+2+6+, M+2+6‐, M+2‐6+, M+2‐6‐, M‐2

+6+, M‐2‐6+, M‐2+6‐and M‐2‐6‐, highlighting a novel aspect of

DLBCL heterogeneity. Among these, the extent of the M+2+6‐sub‐

population robustly identiﬁed unfavourable DLBCL cases across 3

independent cohorts, offering a new deﬁnition of DEL. Interestingly,

the extent of the M+2+6‐sub‐population could be accurately pre-

dicted from individual M, 2, 6 expression data using a mathematical

model, with the predicted extent correlating well with actual coloc-

alization by qIHC. By applying this model to datasets where only

individual expression data was available (gene expression datasets

and a cohort of conventional visually‐scored IHC), we were able to

validate a robust association of the extent of the M+2+6‐subpop-

ulation with poor survival. Importantly, cases with high M+2+6‐

subpopulations were enriched in the newly described MCD and A53

genetic subgroups of DLBCL, consistent with their poorer outcomes.

Conclusions: By investigating single‐cell resolved MYC, BCL2 and

BCL6 co‐expression in DLBCL we have identiﬁed a sub‐population

that robustly predicts prognosis and can reﬁne the traditional deﬁ-

nition of DEL. The mathematical model for estimating sub‐clonal co‐

expression from individual oncogene expression data may be appli-

cable to studies of prognostic markers in multiple cancer types.

The research was funded by: ADJ was supported by the Singapore

Ministry of Health's National Medical Research Council Transition

Award (NMRC/TA/0052/2016). Work in ADJ's laboratory is funded

by a core grant from the Cancer Science Institute of Singapore, Na-

tional University of Singapore through the National Research Foun-

dation Singapore and the Singapore Ministry of Education under its

Research Centres of Excellence initiative, as well as by Singapore

Ministry of Health's National Medical Research Council 'Singapore

lYMPHoma translatiONal studY (SYMPHONY)' Open Fund Large

Collaborative Grant (MOH‐000205‐03).

Keywords: Tumor Biology and Heterogeneity, Aggressive B‐cell non‐

Hodgkin lymphoma, Pathology and Classiﬁcation of Lymphomas

Conﬂicts of interests:pertinent to the abstract

A. D. Jeyasekharan

Consultant or advisory role: Turbine Ltd, AstraZeneca, Janssen and

MSD

Research funding: Janssen and AstraZeneca

Educational grants: Perkin Elmer

098 |NANOSTRING ANALYSIS OF MYCOSIS FUNGOIDES

OFFERS CLUES TO BETTER UNDERSTAND MF PATHOGENESIS

AND PROGRESSION

R. Alonso‐Alonso

, M. Rodriguez

, N. García‐Díaz

, J. P. Vaqué

L. Tomás‐Roca

, L. Cereceda

, S. M. Rodriguez‐Pinilla

, R. Córdoba

J. F. García

, J. L. Rodriguez‐Peralto

, P. Ortiz Romero

, M. Án. Piris

Pinilla

Instituto de Investigación Sanitaria Fundación Jiménez Díaz. CIBERONC,

Pathology, Madrid, Spain,

Universidad de Cantabria.Infección,

Inmunidad & Patología Digestiva, Instituto de Investigación Marqués de

Valdecilla‐IDIVAL , Molecular Biology, Santander, Spain,

Instituto de

Investigación Sanitaria Fundación Jiménez Díaz, Pathology, Madrid, Spain,

Hospital Universitario Fundación Jiménez Díaz. CIBERONC, Haematology,

Madrid, Spain,

Hospital MD Anderson Cancer Center.CIBERONC, Pa-

thology, Madrid, Spain,

Hospital MD Anderson Cancer Center, Pahology,

Madrid, Spain,

Universitario 12 de Octubre, I+12 Research Institute,

Universidad Complutense. CIBERONC, Dermatology, Madrid, Spain

Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are

the most common subtypes of cutaneous T‐cell lymphomas. The

diagnosis of these patients is very challenging and requires an inte-

grated approach, incorporating clinical, morphological, immunophe-

notypic and molecular features. The molecular substrate of early and

advanced stages of MF / SS is still poorly understood and, consequently,

treatment selection is mainly based on clinical data. The study aimed to

transfer what is known about the molecular pathogenesis of MF / SS to

early diagnosis, prognosis, and selection of therapy by identifying

molecular markers associated with the course of the disease.

Methods: Using the NanoString platform for gene‐expression anal-

ysis, we design a custom panel of 77 genes relevant in the patho-

genesis of MF/SS, together with genes known to be therapeutic

targets. A series of 81 formalin‐ﬁxed, parafﬁn‐embedded (FFPE)

samples belonging to 27 MF/SS patients in different phases of the

disease are included in the study.

Results: The technique was informative in all analyzed cases, inde-

pendently of the clinical or histological stage or density of the tumor

inﬁltration. For each case or sample the analysis provided an objec-

tive measure of the T‐cell phenotype (T‐cell differentiation gene

sets), cellular composition of the inﬁltrate (dendritic cells, macro-

phages, B‐cells,…) expression of markers used for therapy selection

(CD30,CXCR4 and KIR3DL2) and expression level of surrogate

markers for the main cell‐survival oncogenic pathways.

Unexpectedly, non‐supervised clustering showed that most of

the clustering was dependent of the patient identity, suggesting that

154

SUPPLEMENT ABSTRACTS

MF/SS has a high degree of inter‐tumoral heterogeneity and that

molecular signature for each patient tends to remain relatively stable

along the disease.

Samples corresponding to pre‐MF lesions tend to cluster with

early MF/SS samples, suggesting that pre‐MF lesions indeed corre-

spond to early phases of the disease.

On the other hand, patients who progress to advanced stages

have a tendency to cluster with each other. Several differentially

expressed genes were comparing early and advanced stages. FGFR3,

NUAK1, FJX1, CXCL12 and RORC were up regulated in early lesions,

while CARD11, CD2, CD38, CD3D, CD3E, CD3G, CXCR4, GZMA, IL10

and SELL were up ‐regulated in tumors (p <0,005).

Conclusions: Gene‐expression proﬁling using a customized Nano-

String platform can be applied to routine parafﬁn embedded MF/SS

samples and provides data that allow to a better understanding of

MF genesis and progression. MF/SS samples show an unexpected

high degree of inter‐tumoral heterogeneity, suggesting that every

patient has some individual molecular signature features that are

found in consecutive biopsies.

The analysis brings also particular gene signatures associated

with early MF and progression, allowing recognizing stage‐speciﬁc

signatures.

EA ‐previously submitted to regional or national meetings (up to

1000 attendees)

The research was funded by: The research was supported by grants

from Instituto de Salud Carlos III, from Ministerio de Economía,

Industria y Competitividad, Asociación Española Contra el Cáncer

(AECC), Comunidad Autónoma de Madrid and Centro de Inves-

tigación Biomédica en Red de Cáncer (CIBERONC): SAF2013‐

47416‐R, CIBERONC‐ISCIII, ISCIII‐MINECO‐AES‐FEDER (Plan

Estatal I +D+I 2013‐2016), AECC PROYE18054PIRI, CAM B2017/

BMD‐3778, PIC97/2017_FJD, PIE15/0081, PIE16/01294 and PIE19/

00715.

L.Tomas‐Roca was funded by Marie Skłodowska‐Curie Individual

Fellowship (No 882597)

Keywords: Genomics, Epigenomics, and Other ‐Omics, Diagnostic

and Prognostic Biomarkers, Cutaneous non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

M. Án. Piris Pinilla

Consultant or advisory role: Millenium/Takeda. Celgene. Gilead.

Jansen. Nanostring. Kyowa Kirin

Research funding: Millenium/Takeda. Gilead. Kura

099 |9P GAIN PREDICTS OUTCOMES IN PATIENTS WITH

RELAPSED/REFRACTORY (R/R) DIFFUSE LARGE B‐CELL

LYMPHOMA (DLBCL) TREATED WITH R‐GEMOX +/‐

ATEZOLIZUMAB. ARGO: A RANDOMISED PHASE II STUDY

A. Davies

, P. McKay

, W. Osborne

, L. Stanton

, O. Tansley‐Hancock

M. Lawrence

, K. Mercer

, A. Allen

, B. Pottinger

, A. Zhelyazkova

F. Miall

, J. Rafferty

, B. Sale

, F. Cucco

, L. Nunn

, A. Coleman

G. Grifﬁths

, M. Q. Du

, C. Burton

, S. Barrons

, P. Johnson

University of Southampton, Southampton Cancer Research UK (CRUK)

Centre, CRUK/NIHR Experimental Cancer Medicines Centre, CRUK

Southampton Clinical Trials Unit, Southampton, UK,

Beatson West of

Scotland Cancer Centre, Department of Haematology, Glasgow, UK,

Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation

Trust, Department of Haematology, Newcastle, UK,

Royal Cornwall

Hospitals NHS Trust, Department of Haematology, Truro, UK,

The

Pennine Acute Hospitals NHS Trust, Department of Haematology,

Manchester, UK,

University Hospitals of Leicester NHS Trust,

Department of Haematology, Leicester, UK,

Patient Representative, c/o

CRUK Southampton Clinical Trials Unit, Southampton, UK,

University of

Cambridge, Department of Pathology, Cambridge, UK,

Leeds Cancer

Centre, Haematological Malignancies Diagnostic Service, Leeds, UK

Introduction: Outcomes for transplant ineligible R/R DLBCL pts are

poor. Atezolizumab (A), a humanised anti PD‐L1 with limited single

agent activity in DLBCL, may provide a novel mechanism to improve

outcomes from rituximab (R), gemcitabine (Gem) and oxaliplatin (Ox)

(R‐GemOx) immunochemotherapy. Chemotherapy may reduce reg-

ulatory T‐cell activity, enhance cross‐presentation of tumour anti-

gens and induce PD‐L1 expression. This leads to synergistic clinical

activity in some solid tumours.

Methods: ARGO was an open‐label randomised phase II trial with a

3:1 randomisation favouring the experimental arm (Arm B) with no

formal planned direct arm comparison. Stratiﬁcation was by R/R sta-

tus. R‐GemOx was delivered for 6 cycles on a 14‐day schedule: R cycle

1 IV 375mg/m

, cycle 2‐6 sc 1400mg; Gem 1000mg/m

; Ox 100mg/m

with GCSF support (Arm A). In Arm B A 840mg IV was added every 14

days from cycle 2 onwards, responding pts continued with A at 840mg

every 21 days for 8 cycles. The primary endpoint was 1‐year pro-

gression free survival (PFS), aiming for ≥40%, to exclude a rate <25%.

The study planned to recruit 112 pts but stopped early on the

recommendation of the Data Monitoring Committee due to failure to

reach the prespeciﬁed futility boundary.

Results: Between July 2018 and June 2020, 53 transplant ineligible

DLBCL pts were enrolled (Arm A n =12 Arm B n =41). The median

age was 73 years (23‐85), median previous lines of therapy was 1 (1‐

7). 74% had IPI ≥3 at entry, 58% refractory, 42% relapsed. Three pts

were double hit, 21 double expressors and 16 ABC. TP53 was

mutated in 44%. 72% of pts completed 6 cycles of induction therapy,

10 withdrawals due to progressive disease (PD), 4 subject/investi-

gator withdrawals, 1 death (pneumonia). The overall response rate

(ORR) was 38% (CR 13%) in Arm B and 27% (CR 9%) in Arm A. Of 16

pts that started maintenance, 63% (10 pts) prematurely stopped (5

PD, 4 trial cessation and 1 proceeded to high‐dose therapy). PFS at

12 months was 15.2% (95%CI 5.8‐28.8) in Arm B and 8.3% (95%CI

0.51‐31.1) with R‐GemOx alone. Overall survival at 12 months:

53.9% (95%CI 37.0‐68.1) Arm B, 58.3% (95%CI 27.0‐80.1) Arm A.

Grade ≥3 toxicity in ≥10% patients was thrombocytopenia (Arm A

25% Arm B 32%) and neutropenia, pneumonia and pyrexia (Arm A

0% Arm B 10% each). In Arm B, ORR, PFS and OS were higher in

SUPPLEMENT ABSTRACTS

155

tumours with gain of PD‐L1 locus at 9p by FISH (10/29), median PFS

7.2 months 9p gain vs 3.2 months normal P =0.037, median OS not

reached in gain 9p vs 5 months P =0.025. This was not reﬂected in

protein expression by immunohistochemistry. There was no differ-

ence in outcome by peripheral blood immune effector cell numbers,

double expressor status or cell of origin.

Conclusions: The efﬁcacy of R‐GemOx was disappointing and not

improved by the addition of A. Further evaluation in pts with PD‐L1

gain at 9p is warranted. Funding support from Roche, endorsed by

CRUK (CRUKE/16/028). A UK National Cancer Research Institute

Lymphoma Group study.

The research was funded by: F. Hoffmann‐La Roche

Keywords: Aggressive B‐cell non‐Hodgkin lymphoma, Combination

Therapies

Conﬂicts of interests pertinent to the abstract

A. Davies

Consultant or advisory role: Celgene, Roche, Gilead/Kite Pharma,

Takeda, Kayropharma, Incyte, VelosBio

Honoraria: Celgene, Roche, Gilead/Kite Pharma, Takeda, Janssen,

Acerta Pharma, AstraZeneca, ADC Therapeutics, Incyte, VelosBio

Research funding: Celgene, Roche, Gilead/Kite Pharma, Takeda, Jans-

sen, Kayropharma, Acerta Pharma, AstraZeneca, ADC Therapeutics

Educational grants: Celgene, Roche

P. McKay

Consultant or advisory role: TAKEDA, Roche, Celgene, Kite and

Beigene

Honoraria: TAKEDA, Roche, Celgene, Kite and Beigene

W. Osborne

Consultant or advisory role: Roche, Takeda, Servier, Kite Gilead,

MSD, Novartis, Beigene, Syneos, Autolus

Honoraria: Pﬁzer, Astra Zeneca, Roche, Takeda, Kite Gilead, Novartis,

Kyowa Kirin

Educational grants: Novartis, Takeda, Pﬁzer, Roche

F. Miall

Consultant or advisory role: Roche and Takeda

Honoraria: Roche and Takeda

G. Grifﬁths

Research funding: Jannsenn‐Cilag, AZ, Novartis, Astex, Roche,

Heartﬂow, BMS, BionTech

Other remuneration: Celldex

C. Burton

Consultant or advisory role: Roche

P. Johnson

Consultant or advisory role: Epizyme, Janssen, Oncimmune, Boeh-

ringer Ingelheim

Honoraria: Bristol Myers Squibb, Celgene, Genmab, Incyte, Kite

Pharma, Kymera, MorphoSys, Novartis, Takeda

Research funding: Epizyme

100 |MOLECULAR HIGH GRADE (MHG) GENE EXPRESSION

PROFILE IN DLBCL IS ENRICHED AMONG PATIENTS WITH EARLY

TREATMENT FAILURE

S. L. Barrans

, F. Cucco

, J. Davies

, M. van Hoppe

, T. Mell

, K.

Mercer

, l. Stanton

, J. Caddy

, R. Tooze

, C. Burton

, D. Westhead

M. Du

, A. Davies

, P. Johnson

Leeds Teaching Hospitals, HMDS, Institute of Oncology, Leeds, UK,

University of Cambridge, Department of Pathology, Cambridge, UK,

University of Leeds, Bioinformatics Group, Faculty of Biological sciences,

Leeds, UK,

University of Southampton, SCTU, Southampton, UK,

University or Leeds, School of medicine, Leeds, UK,

University of

Southampton, Medicine, Southampton, UK

Diffuse large B cell lymphoma (DLBCL) is biologically and clinically

heterogenous, with variable response to standard treatment. We

previously described a subgroup of DLBCL with a GCB‐like gene

expression signature similar to that of Burkitt lymphoma and

156

SUPPLEMENT ABSTRACTS

enriched for ‘double hit’ FISH status. This molecular high grade

(MHG) subset of patients was identiﬁed from the REMoDL‐B trial

using Illumina WG‐DASL data and showed an inferior response to R‐

CHOP,

conﬁrmed in our population based cohort.

The MaPLe trial (Molecular Proﬁling for Lymphoma) is a multi-

centre prospective observational cohort study for the collection of

tumour samples from patients with DLBCL, with almost 3000 sam-

ples now collated.

The aim of this analysis was to characterise lymphomas that

progressed early according to gene expression proﬁling (GEP) status,

including MHG and cell of origin (COO), as well as double hit FISH

status and targeted sequencing.

Patients who progressed within 6 months of MaPLe study baseline

visit were identiﬁed. To allow assessment of biological variables which

may contribute to treatment failure, each case was matched to another

patient who had not progressed within 6 months based on age and IPI

score at diagnosis. Samples with sufﬁcient material were interrogated

using the HTG EdgeSeq Pan B‐Cell Lymphoma Panel and classiﬁed

according to MHG and COO status. Targeted sequencing of 191 gene/

region targets using TWIST library prep, sequenced on an Illumina

HiSeq was also performed and FISH for double hit status is underway.

Thirty nine eligible patients were identiﬁed as ‘early progressors’

and matched to 39 controls. HTG data was available and passed QC

metrics in 64 patients (32 from each group). In total, 18/64 (28%)

were classiﬁed as MHG, with 12/18 of these (67%) represented

within the early progressor group. This is signiﬁcantly higher than the

prevelance of MHG previously demonstrated in REMoDL‐B and

population based datasets, reﬂecting the case selection within this

study. ABCs were evenly distributed between groups (11/21 vs 10/

21) while GCBs and unclassiﬁable samples were slightly more prev-

alent in the control group (7/18 vs 11/18 and 2/7 vs 5/7 respec-

tively). Relevant mutations, previously described to be associated

with ABC, GCB and MHG, were demonstrated within the GEP sub-

groups, however there was no signiﬁcant association between indi-

vidual or subtype‐speciﬁc mutations and progression.

The results of this study conﬁrm that the MHG gene expression

proﬁle can be reproduced using HTG EdgeSeq Pan B‐Cell Lymphoma

Panel data. MHG was more frequently identiﬁed in the early pro-

gressor cohort, suggesting that MHG GEP contributes to poor

response to conventional R‐CHOP treatment for DLBCL. Prospective

identiﬁcation of this group for testing more effective treatment

strategies is a priority.

1. Sha et al. J Clin Oncol. 2019;37(3):202‐212

2. Painter et al. BJH 2019;185(4):781‐784

The research was funded by: Bloodwise (Blood Cancer UK)

Keywords: Diagnostic and Prognostic Biomarkers, Aggressive B‐cell

non‐Hodgkin lymphoma, Pathology and Classiﬁcation of Lymphomas

Conﬂicts of interests pertinent to the abstract

P. Johnson

Consultant or advisory role: Takeda, Bristol‐Myers Squibb, Novartis,

Genmab, InCyte, Morphosys, Kymera

Research funding: Janssen, Epizyme

101 |CHARACTERIZATION OF THE GENETIC LANDSCAPE OF

HIGH‐GRADE B‐CELL LYMPHOMA, NOS – AN LLMPP PROJECT

B. J. Collinge

, L. K Hilton

, J. Wong

, S. Ben‐Neriah

, C. K. Rushton

G. W. Slack

, P. Farinha

, J. R. Cook

, G. Ott

, A. Rosenwald

, E.

Campo

, C. Amador

, T. C. Greiner

, P. W. Raess

, J. Y. Song

, G.

Inghirami

, E. S. Jaffe

, D. D. Weisenburger

, W. C. Chan

, H.

Holte

, K. Beiske

, K. Fu

, J. Delabie

, S. Pittaluga

, A. L. Feld-

man

, K. J. Savage

, A. J. Mungall

, L. M. Staudt

, C. Steidl

, L. M.

Rimsza

, R. D. Morin

, D. W. Scott

BC Cancer, Centre for Lymphoid Cancer, Vancouver, Canada,

Simon Fraser University, Molecular Biology and Biochemistry,

Burnaby, Canada,

Cleveland Clinic, Department of Molecular Pathology

and Laboratory Medicine, Cleveland, Ohio, USA,

Robert‐Bosch‐

Krankenhaus and Dr. Margarete Fischer‐Bosch Institute of Clinical Phar-

macology, Department of Clinical Pathology, Stuttgart, Germany,

Uni-

versity of Wuerzburg, Institute of Pathology, Wuerzburg,

Germany,

Hospital Clinic of the University of Barcelona, Department of

Pathology, Barcelona, Spain,

University of Nebraska Medical Center,

Department of Pathology and Microbiology, Omaha, Nebraska, USA,

Oregon Health & Science University, Department of Pathology, Portland,

Oregon, USA,

City of Hope National Medical Center, Department of Pa-

thology, Duarte, California, USA,

Weill Cornell Medicine, Pathology and

Laboratory Medicine, New York, New York, USA,

National Cancer Insti-

tute, Laboratory of Pathology, Bethesda, Maryland, USA,

Oslo University

Hospital, Department of Oncology, Oslo, Norway,

Oslo University Hos-

pital, Department of Pathology, Oslo, Norway,

Roswell Park Cancer

Institute, Department of Pathology & Laboratory Medicine, Buffalo, New

York, USA,

University Health Network and University of Toronto,

Department of Laboratory Medicine and Pathobiology, Toronto, Canada,

Mayo Clinic College of Medicine, Laboratory Medicine and Pathology,

Rochester, Minnesota, USA,

BC Cancer, Canada's Michael Smith Genome

Sciences Centre, Vancouver, Canada,

National Cancer Institute, Center

for Cancer Research, Bethesda, Maryland, USA,

Mayo Clinic, Department

of Laboratory Medicine and Pathology, Scottsdale, Arizona, USA

Introduction: High‐grade B‐cell lymphoma encompasses (1) tumours

with MYC and BCL2 and/or BCL6 rearrangement (HGBL‐DH/TH),

and (2) tumours lacking this combination of rearrangements but

displaying “high‐grade” morphology (HGBL‐NOS) – blastoid or

morphology intermediate between diffuse large B‐cell lymphoma

(DLBCL) and Burkitt lymphoma (BL). Limited by the rarity of HGBL‐

NOS, it remains unclear whether these tumours share a unifying

biology and/or bear molecular similarity to HGBL‐DH/TH. This un-

certainty is further confounded by interobserver variability in

morphological assessment and artifacts introduced during tissue

ﬁxation. Here, we aim to characterize the molecular features of

HGBL‐NOS, as conﬁrmed by central pathology review (CPR) by a

panel of expert lymphoma pathologists, to determine if it represents

a biologically distinct subset of tumours.

Methods: Archival diagnostic tissue biopsies from 93 HGBL‐NOS

tumours were submitted from LLMPP sites, with ﬂuorescent in situ

hybridization (FISH) testing for MYC,BCL2 and BCL6 to exclude

SUPPLEMENT ABSTRACTS

157

HGBL‐DH/TH. CPR has been completed for 61 tumours. Cell‐of‐

origin (COO) and double hit signature (DHITsig) were determined

by gene expression proﬁling. Recurrent somatic mutations (SNVs/

Indels) were identiﬁed from the intersection of three out of four

predictions by Strelka2, LoFreq, Mutect2 and SAGE on whole

genome or exome sequencing of 46 tumours. Genetic subtypes were

assigned using the LymphGen data portal.

Results:MYC rearrangement was detected in approximately half of all

identiﬁed tumours, while a similar but not fully overlapping proportion

were DHITsig+. Cases spanned the GCB (56%) and ABC (28%) COO

subgroups, with 16% unclassiﬁed. Following CPR, nearly half of tu-

mours were reclassiﬁed as DLBCL (44%) or BL (5%). The frequency of

MYC rearrangement and the distribution of COO subgroups was

similar between tumours conﬁrmed as HGBL‐NOS and those reclas-

siﬁed as DLBCL, while 55% of conﬁrmed HGBL‐NOS were DHITsig+

compared with 39% of reassigned tumours. Few recurrently mutated

genes were shared among conﬁrmed HGBL‐NOS tumours and no

differentially mutated genes were identiﬁed through comparison to

tumours reclassiﬁed as DLBCL. While most tumours were unclassiﬁed

by the LymphGen algorithm, the remainder were spread across EZB

(13%), MCD (9%), ST2 (7%), and BN2 (4%).

Conclusion: The high reclassiﬁcation rate highlights the difﬁculty in

distinguishing high‐grade morphology, while the lack of shared mo-

lecular features among CPR conﬁrmed HGBL‐NOS suggests this

morphological distinction identiﬁes a heterogeneous group of tu-

mours. Furthermore, these tumours appear to be largely unrelated to

HGBL‐DH/TH‐BCL2, which are almost all uniformly EZB, GCB and

DHITsig+. Further molecular characterization and comparisons to

related entities is required to determine how these tumours are best

classiﬁed.

158

SUPPLEMENT ABSTRACTS

Keywords: Genomics, Epigenomics, and Other ‐Omics, Aggressive B‐

cell non‐Hodgkin lymphoma, Pathology and Classiﬁcation of

Lymphomas

No conﬂicts of interest pertinent to the abstract.

102 |RNA SEQUENCING REVEALS DIFFERENT GENE

EXPRESSION IN MALE VERSUS FEMALE DIFFUSE LARGE B‐CELL

LYMPHOMA

P. Ghione

, E. Cortes Gomez

, P. Torka

, S. Sundaram

, C. Mavis

, F.

Tabbo'

, J. Gu

, M. T. Cacciapuoti

, L. Yoffe

, J. Wang

, F. Hernandez‐

Ilizaliturri

, G. Inghirami

Roswell Park Comprehensive Cancer Center, Lymphoma, Buffalo, NY,

USA,

Roswell Park Comprehensive Cancer Center, Biostatistics, Buffalo,

New York, USA,

Universita' degli Studi di Torino, Oncology, Torino, Italy,

Weill Cornell Medicine, Hematopathology, New York, USA,

Weill Cornell

Medicine, Biostatistics, New York, New York, USA

Introduction: Male gender is known to represent a risk factor for

survival, in several lymphoma subtypes (Lim, Loy et al. 2015, Nabhan,

Zhou et al. 2016). This is well established in Hodgkin's(Hasenclever and

Diehl 1998) and follicular lymphoma (Federico, Vitolo et al. 2000, Solal‐

Céligny, Roy et al. 2004), where male (M) gender has been included as a

prognostic factor in some of the prognostic indices. Moreover, large

cohorts of diffuse large B cell lymphoma (DLBCL) show that female (F)

experience longer progression‐free survival (Junlén, Lockmer et al.

2020), with signiﬁcant differences between genders in pts >60 years

old in the rituximab era(2014). Recent data have also demonstrated

that F with DLBCL have superior responses and longer duration to

anti‐CD19 CAR‐T cell therapy than M counterparts (Nastoupil, Jain

et al. 2020). The biological phenomena behind these clinical differences

remain unknown. We hypothesized that differences in gene expression

in M and F might explain patients’ outcomes in F DLBCL.

Methods: We analyzed total RNA sequencing (RNAs) data as previ-

ously described (Treater M, Nat Commun 2018) from frontline naïve

DLBCL treated with R‐CHOP‐like regimens, enriched for relapsed/

refractory cases (n =23 r/r, 32 sensitive). DESeq2 (v1.30.1) was used

with a 2 �2 factor design involving gender and treatment response (r/r

vs non‐r/r) to identify differentially expressed genes. A gene with FC >

1.5 and FDR <0.05 was considered as statistically signiﬁcant. The

obtained gene lists were further reﬁned by removing genes known to

be preferentially expressed in M or F. The list was tested for pathway

enrichment analysis against MSigDB's Hallmark and C2CP databases

using Fisher's exact test. Signiﬁcant pathways are chosen after multiple

test adjustment with cut‐off value of FDR <0.05.

Results: Among 55 naïve DLBCL cases, 23 were F (11 r/r, 12 non‐r/

r), 34 M (12 r/r, 20 non‐r/r). The top 50 genes up‐regulated or

down‐regulated in F were stratiﬁed and sorted in columns grouping

r/r and non‐r/r cases for each gender. Genes such as SMC1B,

TCL1B, MSTN were up‐regulated in F, while BCORP1, CCNA1, AK5

were up‐regulated in M. Pathways evaluation showed that TGFbeta,

TP53 and IL6‐JAK/STAT3 were upregulated speciﬁcally in r/r F,

whereas MYC, E2F, PI3K/AKT/MTOR were selectively up‐regulated

in non‐r/r F cases. Intriguingly, both these sets of pathways were

down‐regulated in M cases. Further analysis is ongoing and will be

presented.

Conclusions: We demonstrate that F and M DLBCL have differential

gene expression proﬁling and putative activation of selected path-

ways. Further exploration and validation of these differences in

larger cohorts can lead to a better understanding of the therapeutic

variability noted between the two genders.

Keywords: Pathology and Classiﬁcation of Lymphomas

No conﬂicts of interest pertinent to the abstract.

103 |TESTICULAR DIFFUSE LARGE B‐CELL LYMPHOMA:

CLINICO‐BIOLOGICAL CHARACTERIZATION, EVALUATION OF

TREATMENT RESPONSE AND SURVIVAL

A. Rivas‐Delgado

, C. López

, F. Nadeu

, M. Grau

, A. Rivero

, J.

Bosch

, M. Alcoceba

, T. Gustavo

, L. Luizaga

, C. Barcena

, N. Kel-

leher

, S. Martin

, P. Mozas

, O. Balague

, G. Frigola

, L. Magnano

, T.

Baumann

, N. Villamor

, A. Muntañola

, J. M. Sancho

, A. Martin

García‐Sancho

, E. Gonzalez‐Barca

, F. Climent

, E. Campo

, E. Giné

A. López‐Guillermo

, S. Beà

Hospital Clínic de Barcelona, Hematology and Pathology Departments,

Barcelona, Spain,

Instituto de Investigaciones Biomédicas August Pi i

Sunyer (IDIBAPS), Molecular pathology of lymphoid neoplasms, Barcelona,

Spain,

Hospital de Bellvitge, IDIBELL, Pathology Department, Barcelona,

Spain,

Hospital Universitario de Salamanca, Hematology Department,

Salamanca, Spain,

ICO‐IJC‐Hospital Universitari Germans Trias i

Pujol, Hematology and Pathology Departments, Badalona, Spain,

Hospital

Universitari Mutua de Terrassa, Hematology and Pathology Departments,

Terrasa, Spain,

Hospital Universitario 12 de Octubre, Hematology

and Pathology Departments, Madrid, Spain,

Institut Català d'Oncologia‐

Hospital de Palamos, Hematology Department, Girona, Spain,

Institut

Català d’Oncologia‐Hospital Duran i Reynals, IDIBELL, Universitat de

Barcelona, Hematology Department, L'Hospitalet de Llobregat, Spain

Background: Testicular diffuse large B‐cell lymphoma (T‐DLBCL) is

an infrequent and aggressive lymphoma accounting for 1‐2% of all

non‐Hodgkin's lymphomas. Although prognosis improved with the

introduction of rituximab, the outcome of these patients is still poor.

This study aimed to analyze the clinical features and outcome of a

series of T‐DLBCL as well as to characterize their genomic proﬁle.

Methods: We collected 62 patients with T‐DLBCL diagnosed be-

tween 2002 and 2020. DNA was extracted from formalin‐ﬁxed

parafﬁn‐embedded (FFPE) tissue biopsies. Copy number alterations

(CNA) were studied using OncoScanTM CNV FFPE arrays (Thermo-

ﬁsher) (n =17) and gene mutations by a B‐cell malignancy‐oriented

targeted next‐generation sequencing (NGS) panel containing 121

genes (SureSelectXT, Agilent Technologies) (n =15). The genomic

status of BCL2,BCL6,MYC, and JAK2 locus was also investigated by

FISH in 33 cases.

SUPPLEMENT ABSTRACTS

159

Results: Median age at diagnosis was 69 (30‐89) years. Sixty‐seven

percent of the cases had stages I/II, 72% low‐or low‐intermediate‐

risk IPI, and 84% (32/39) showed a non‐germinal center phenotype

(Hans algorithm). In 15 patients with available NGS, the most

frequently mutated genes were MYD88

L265P

(67%), PIM1 (60%),

KMT2D (60%), CD79B (40%), CREBBP (33%), and TBL1XR1 (47%)

(Figure 1A). Of note, none of the patients with localized stages had

CIITA mutations (p =0.011). MYC,BCL2, and BCL6 rearrangements

were observed in 0%, 9%, and 31% of cases by FISH, respectively. We

detected CNA in all samples with a median of 13 alterations per case

(range, 1‐33), including a median of 6 gains (1‐25), 6 losses (0‐13),

and 3 copy neutral loss of heterozygosity (CN‐LOH) (0‐8). The most

frequent CNA were trisomy 7 (18%) and 18 (18%); gains of 1q (47%),

3 (35%), 6p (29%), 9p24.3‐p24.1 (18%), 9p13.2 (29%), 12p13.33‐

q21.1 (18%), 17q (24%), 18q (29%), and 19q13.32‐q14.43 (35%); and

losses of 9p21.3 (CDNK2A/B) (59%), 6q21 (PRDM1) (76%), 6q22.31‐

160

SUPPLEMENT ABSTRACTS

q24.3 (TNFAIP3) (65%), 13q14.2 (DLEU2) (18%) and 17p (TP53) (35%)

(Figure 1B). CN‐LOH of 9p region was recurrent in 35% of cases.

Moreover, using FISH for JAK2 (9p24) we detected gain in one

additional case, corresponding to a total of 4 cases (24%).

All but ﬁve patients received ﬁrst‐line treatment with immu-

nochemotherapy, mostly R‐CHOP (86%), followed by radiotherapy in

63%. Central nervous system prophylaxis was performed in 79% of

the patients. Complete response rate was 78%. With a median

follow‐up of 8 years, eleven patients relapsed, 3 at CNS. Progression‐

free survival at 5 years was 45% (95% CI: 32‐62). Thirty‐three (53%)

patients died. Overall survival at 5 years was 50% (95% CI: 37‐67).

Conclusions: T‐DLBCL is a poor risk type of DLBCL with a typical

non‐GCB subtype although with particular genetic features.

The research was funded by: This work was supported by the Insti-

tuto de Salud Carlos III, the Ministerio de Ciencia e Innovación and

the European Regional Development Fund “Una manera de hacer

Europa” [grants numbers PI16/00420 and PI19/00887 to ALG and

EG and PI17/01061 to SB ]; CIBERONC [grants numbers CB16/12/

00334 and CB16/12/00225]; Fundación AECC/CIBER [grant number

PROYE18020BEA]. CL is supported by Agència de Gestió d'Ajuts

Universitaris i de Recerca (AGAUR) [grant number 2018‐BP‐00055].

Keywords: Aggressive B‐cell non‐Hodgkin lymphoma, Extranodal

non‐Hodgkin lymphoma, Pathology and Classiﬁcation of Lymphomas

No conﬂicts of interest pertinent to the abstract.

104 |A GENE SIGNATURE TO PREDICT RISK OF

TRANSFORMATION IN PATIENTS WITH FOLLICULAR

LYMPHOMA

I. Fernandez‐Miranda

, M. Dominguez

, L. Pedrosa

, S. Gomez

, J.

Gonzalez‐Rincon

, B. Espinet

, F. Climent

, F. de la Cruz

, P. Martin‐

Acosta

, L. Colomo

, A. Salar

, M. Garcia‐Cosio

, F. R. Garcia‐Arroyo

M. Llanos

, N. Yanguas

, S. Sequero

, S. Mercadal

, B. Navarro

, M.

A. Piris

, M. Mollejo

, M. Provencio

, M. Sanchez‐Beato

Instituto de Investigación Sanitaria Puerta de Hierro‐Segovia de Arana,

Lymphoma Research Group, Majadahonda, Spain,

Hospital del Mar,

Pathology Service, Barcelona, Spain,

Hospital Universitari de Bellvitge‐

IDIBELL, Pathology Department, Bellvitge, Spain,

Hospital Universitario

Virgen del Rocío, Hematology Department, Sevilla, Spain,

Instituto de

Investigación Sanitaria Puerta de Hierro‐Segovia de Arana, Research

Group in Molecular Cancer Pathology, Majadahonda, Spain,

Hospital del

Mar, Hematology Service, Barcelona, Spain,

Hospital Universitario

Ramón y Cajal, Pathology Department, Madrid, Spain,

Complejo Hospi-

talario de Pontevedra, Oncology Department, Pontevedra, Spain,

Hos-

pital Universitario de Canarias, Oncology Department, Tenerife, Spain,

Hospital Universitario San Cecilio, Oncology Department, Granada,

Spain,

Institut Catala d’Oncologia‐IDIBELL, Clinic Hematology Depart-

ment, Bellvitge, Spain,

Hospital Universitario Puerta de Hierro, Hema-

tology Department, Majadahonda, Spain,

Hospital Fundación Jiménez

Díaz, Pathology Department, Madrid, Spain,

Complejo Hospitalario de

SUPPLEMENT ABSTRACTS

161

Toledo, Pathology Department, Toledo, Spain,

Hospital Universitario

Puerta de Hierro, Oncology Department, Majadahonda, Spain

Follicular lymphoma (FL) is an indolent but mainly incurable disease.

Histological transformation to diffuse large B cell lymphoma is

associated with rapid progression, treatment resistance and poor

prognosis. The ability to identify patients at higher risk of trans-

formation at the time of diagnosis would imply a relevant advance.

Prospective identiﬁcation of transformation‐potential would also

serve for guiding treatment and monitoring of patients. We aimed to

validate the prognostic signature previously identiﬁed by our group

(González‐Rincón et al., 2019) to stratify patients according to their

risk of transformation.

We conducted targeted massive parallel sequencing (including

77 genes) on new diagnostic samples from 21 pre‐transformed (pre‐

tFL) and 30 non‐transformed FL (ntFL) patients. Additionally, our

previously published cohort of 42 samples (22 pre‐tFL and 20 ntFL)

was included to enable risk analysis. Cox proportional hazards

regression and Kaplan‐Meier analysis were performed joining both

cohorts (93 samples) to develop risk models.

Comparative analysis revealed that pre‐tFL showed more mu-

tations than ntFL samples (9.5 vs. 8). The variant allele frequency

(VAF) in pre‐tFL samples was lower than in ntFL (pre‐tFL: 24% vs.

ntFL: 30%; t‐test p <0.001), resulting in a higher proportion of

subclonal mutations (<20% VAF) per sample (pre‐tFL: 38% vs. ntFL:

24%; t‐test p =0.034). Importantly, patients with subclonal muta-

tions had a higher risk of transformation (p =0.022) by the univariate

Cox analysis. The detection of mutations in HIST1H1E (p <0.001),

NOTCH2 (p <0.001), IRF8 (p =0.005) and UBE2A (p =0.006)

(HIST1H1E,NOTCH2 &UBE2A previously reported by González‐

Rincón et al., 2019) were statistically associated with transformation

by the multivariate Cox analysis. Inclusion of the Follicular

Lymphoma International Prognostic Index (FLIPI) into the multivar-

iate Cox model (intermediate FLIPI: p =0.024; high FLIPI: p =0.001;

HIST1H1E: p <0.001; NOTCH2: p =0.002; UBE2A: p =0.012; IRF8:

p=0.029) rendered a classiﬁcation of the samples into three risk

groups, with distinct transformation probabilities at 5 years (85% for

the high‐risk group, 46% for the intermediate‐risk group and 22% for

the low‐risk group; p <0.001) by the Kaplan‐Meier analysis.

In summary, genomic analysis on FL samples have enabled the

association of mutated genes with higher risk of transformation. We

have also demonstrated that mutations below 20% VAF in FL sam-

ples at diagnosis are associated with transformation. Integration of

the mutational status with clinical risk factors into a predictive model

improves the risk stratiﬁcation and could be useful for identifying

patients at higher risk of transformation.

The research was funded by: The ISCIII‐MINECO AES‐FEDER (Plan

Estatal de I+D+I 2008‐2011 and 2013‐2016) (DTS17/00039, PI17/

00272); GILEAD (GL18/00019) and Comunidad de Madrid (B2017/

BMD‐3778). Centro de Investigación Biomédica en Red de Cáncer

(CIBERONC) (CB16/12/00291)

Keywords: Genomics, Epigenomics, and Other ‐Omics, Risk Models,

Indolent non‐Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

105 |MUTATIONAL LANDSCAPE OF MARGINAL ZONE B‐CELL

LYMPHOMAS OF VARIOUS ORIGIN: ORGANOTYPIC

ALTERATIONS AND DIAGNOSTIC POTENTIAL FOR ASSIGNMENT

OF ORGAN ORIGIN

S. Dirnhofer

, V. Vela

, D. Juskevicius

, T. Menter

, A. Tzankov

University Hospital Basel, Pathology, Basel, Switzerland

162

SUPPLEMENT ABSTRACTS

Background: Marginal zone lymphomas (MZL) comprise nodal

(NMZL), splenic (SMZL), and extranodal (EMZL) variants, accounting

for 10%, 15% and 75%, respectively. MZL have no disease‐deﬁning

phenotype and the diagnostic borders among each other and to

other small B‐cell lymphomas are blurred. In disseminated cases,

determination of MZL origin can be impossible. MZL are known

to bear rather typical site‐of‐origin translocations, yet their muta-

tional landscape at the nucleotide level has not been integratively

analyzed.

Methods: This meta‐analysis aims to concisely summarize the ge-

netic landscape with respect to somatic mutations of NMZL, EMZL

(dura mater, ocular adnexa, salivary glands, thyroid, lung, stomach,

skin) and SMZL. A systematic PubMed search for studies reporting

on sequenced MZL was executed. A data‐set containing 25 pub-

lications comprising 6016 variants from 1663 patients was created.

Genomic information was extracted from the selected studies and

uniformed to the GRCh38‐hg38 genome by applying LiftOver ‐

UCSC Genome Browser. The missing information on variants such

as genomic location and reference sequence variant effect anno-

tation was obtained with the GRCh38 assembly of Variant Effect

Predictor by Ensemble and Annovar software. The number of

mutated and unmutated cases was retrieved and calculated from

the variant tables with somatic mutations. A shortlist was gener-

ated for mutated genes with a stringent frequency cut‐off of

>7.5%.

Results: In SMZL, KLF2 (18%, 103/567) and NOTCH2 (16%, 118/

725) were the most frequently mutated genes. Pulmonary MZL

and NMZL displayed recurrent mutations in chromatin‐modifying

genes, especially KMT2D (25%, 13/51, and 20%, 20/98, respec-

tively), next to TNFAIP3 (19%, 12/64, and 14%, 12/88, respec-

tively). Ocular adnexal and dura mater MZL displayed a particular

high frequency of mutations in TNFAIP3 (39%, 113/293, and 45%,

5/11, respectively). MZL of the thyroid had a uniquely high prev-

alence for TET2 mutations (61%, 11/18), next to mutations of

TNFRSF14 (44%, 8/18). Cutaneous MZL showed a particular

accumulation of FAS (63%, 24/38) and SLAMF1 mutations (24%, 9/

38). Finally, TBL1XR1 (24%, 14/58) was the most commonly

mutated gene in MZL of the salivary glands, next to GPR34 (16%,

9/58).

Assigned to pathways and functions, mutations affected NF‐κB and

NOTCH signalling as well as chromatin modiﬁcation. Mutations of

NF‐κB and NOTCH signalling genes were rather mutually exclusive,

with only 140 cases showing co‐occurrence, 553 being exclusively

mutant in either pathway compounds, and 242 being wild‐type (p =

1.07E‐9; Fisher's test); the same applied to NF‐κB member and

chromatin modiﬁer mutations.

Conclusion: Mutations of distinct genes show organ‐of‐origin‐

preferential distribution among MZL which may help assigning MZL

derivation in difﬁcult cases and possibly pave the way for novel

tailored treatment concepts.

Keywords: Pathology and Classiﬁcation of Lymphomas

No conﬂicts of interest pertinent to the abstract.

106 |CYTIDINE DEAMINASES SHAPE THE GENOME OF

GERMINAL CENTER B CELL DERIVED LYMPHOMA

M. Ren

, E. Sidiropoulou

, R. N. Tasakis

, E. Donato

, I. Gonzalez‐

Menendez

, C. E Busse

, T. J Luck

, A. Dolnik

, L. Bullinger

A. Trumpp

, L. Quintanilla‐Martinez

, M. Kreuz

, B. Chapuy

, D.

Hübschmann

, R. Siebert

, F N. Papavasiliou

, S. Sander

German Cancer Research Center (DKFZ)/National Center for Tumor

Diseases Heidelberg (NCT), Division of Adaptive Immunity and

Lymphoma, Heidelberg, Germany,

German Cancer Research Center

(DKFZ), Division of Immune Diversity, Heidelberg, Germany,

German

Cancer Research Center (DKFZ) and DKFZ‐ZMBH Alliance, Division of

Stem Cells and Cancer, Heidelberg, Germany,

Eberhard Karls University

of Tübingen and Comprehensive Cancer Center, Tübingen University

Hospital, Institute of Pathology and Neuropathology, Department of Pa-

thology, Tübingen, Germany,

German Cancer Research Center (DKFZ),

Division of B cell Immunology, Heidelberg, Germany,

Campus Virchow

Klinikum, Berlin, Charité – Universitätsmedizin Berlin, corporate member

of Freie Universität Berlin and Humboldt‐Universität zu Berlin, Depart-

ment of Hematology, Oncology, and Tumorimmunology, Berlin, Germany,

Universität Leipzig, Institute for Medical Informatics, Statistics and

Epidemiology (IMISE), Leipzig, Germany,

University Medical Center

Göttingen, Department of Hematology and Medical Oncology, Göttingen,

Germany,

German Cancer Research Center (DKFZ)/National Center for

Tumor Diseases Heidelberg (NCT), Heidelberg Institute for Stem Cell

Technology and Experimental Medicine (HI‐STEM gGmbH), Heidelberg,

Germany,

Ulm University and Ulm University Medical Center, Depart-

ment of Human Genetics, Ulm, Germany

Introduction: Most human lymphomas have their origin in the

germinal center (GC) reaction where the cytidine deaminase AID

(encoded by the AICDA gene) targets the B cell genome. Although

AID's activity at non‐immunoglobulin (Ig) genes is reported, this off‐

target effect is not the only source of tumorigenic mutations in

lymphoma patients. Thus, we aimed for a better understanding of

AID independent mechanisms of mutagenesis in GC B cell derived

lymphomagenesis.

Methods: Genetic Aicda knockout was combined in a pre‐clinical

mouse lymphoma model characterized by GC B cell speciﬁc MYC

and PI3K co‐activation. In‐depth characterization of pre‐malignant

and malignant GC B cells was achieved by ﬂow cytometry, immu-

nohistology and next generation sequencing technologies. The mu-

rine ﬁndings were conﬁrmed using data derived from human B cells

and lymphoma cells provided by the ICGC MMML‐seq consortium.

Results: In young mice, AID deﬁciency promoted GC formation,

although GC B cell proliferation, survival and differentiation were

similar in AID proﬁcient and deﬁcient animals. Upon aging, GC B cell

derived lymphomagenesis was unperturbed in the absence of AID. In

AID deﬁcient tumors the lack of mutations in Ig genes was in contrast

to the increased mutation load in non‐Ig genes compared to AID

proﬁcient lymphoma. Gene expression proﬁling and the detection of

distinct mutational signatures pointed to the function of the cytidine

deaminase APOBEC1 in murine AID deﬁcient lymphoma.

SUPPLEMENT ABSTRACTS

163

The mining of human data uncovered the expression of APO-

BEC3 family members in human B cells, including APOBEC3B induc-

tion in GC B cells, thereby mimicking murine Apobec1 expression

kinetics. Although APOBEC3B expression levels were variable across

different GC B cell derived lymphoma entities, the positive correla-

tion of its expression and presence of APOBEC related DNA signa-

tures indicates its relevance in human lymphomagenesis.

Conclusions: Our research provides experimental evidence of APO-

BEC mediated DNA mutagenesis in an autochthonous mouse lym-

phoma model and supports these ﬁndings in lymphoma patient data

sets. Thus, we unveiled AID independent transformation in lym-

phoma prone GC B cells and highlight APOBEC enzymes as mutation

driver in GC B cell derived lymphomagenesis.

The research was funded by: the Deutsche Krebshilfe (Max Eder

Program 111349 to S.Sander), the Deutsche Jose Carreras Leukä-

miestiftung (11/2017 to S.Sander), FOR2674, SFB873 funded by the

DFG, the DKTK Joint Funding “RiskY‐AML” and the Dietmar Hopp

Foundation (to A.Trumpp) and SFB1074 funded by the DFG (to R.

Siebert).

Keywords: Tumor Biology and Heterogeneity, Aggressive B‐cell non‐

Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

INDOLENT LYMPHOMAS

107 |SAFETY AND EFFICACY OF ZANUBRUTINIB IN PATIENTS

WITH RELAPSED/REFRACTORY MARGINAL ZONE LYMPHOMA

(MAGNOLIA PHASE 2 STUDY)

J. Trotman

, A. Tedeschi

, K. Linton

, P. McKay

, B. Hu

, H. Chan

, J.

Jin

, M. Sobieraj‐Teague

, P. L. Zinzani

, M. Coleman

, P. Browett

X. Ke

, M. Sun

, R. Marcus

, C. Portell

, C. Thieblemont

, K.

Zhou

, A. M. Liberati

, E. Bachy

, F. Cavallo

, Rég. Costello

, S.

Iyengar

, R. Marasca

, H. Mociková

, J. S. Kim

, D. Talaulikar

M. Co

, W. Zhou

, J. Huang

, S. Opat

Concord Repatriation General Hospital, University of Sydney, Oncology,

Concord, Australia,

ASST Grande Ospedale Metropolitano Niguarda,

Hematology, Milan, Italy,

The Christie, Hematology, Manchester, UK,

Beatson West of Scotland Cancer Centre, Oncology, Glasgow, UK,

Levine Cancer Institute/Atrium Health, Oncology, Charlotte, USA,

North

Shore Hospital, Haematology, Auckland, New Zealand,

The First

Afﬁliated Hospital, Zhejiang University, Hematology, Hangzhou, China,

Flinders Medical Centre, Haematology, Bedford Park, Australia,

Institute

of Hematology “Seràgnoli” University of Bologna, Hematology, Bologna,

Italy,

Clinical Research Alliance, Hematology, Lake Success, USA,

Auckland City Hospital, Haematology, Grafton, New Zealand,

Peking

University Third Hospital, Hematology, Beijing, China,

Institute of

Hematology & Blood Diseases Hospital, Chinese Academy of Medical

Sciences, Peking Union Medical College, Hematology, Tianjin, China,

Sarah Cannon Research Institute UK, Oncology, London, UK,

University of Virginia Health System, Hematology/Oncology,

Charlottesville, USA,

APHP, Hôpital Saint‐Louis, Hemato‐oncology, Paris

University Diderot, Hematology/Oncology, Paris, France,

Henan Cancer

Hospital, Oncology, Zhengzhou, China,

Azienda Ospedaliera Santa

Maria Di Terni, Oncology, Terni, Italy,

Centre Hospitalier Lyon Sud,

Pierre Bénite, Hematology, Rhone, Italy,

Azienda Ospedaliera Città della

Salute e della Scienza di Torino, Hematology, Torino, Italy,

Hôpital de la

Conception – APHM, Hematology, Marseille, France,

Royal Marsden

Hospital, Haematology, London, UK,

AOU Policlinico di Modena, He-

matology, Modena, Italy,

Fakultní nemocnice Královské Vinohrady,

Hematology, Praha 10, Czech Republic,

Severance Hospital, Hematol-

ogy, Seoul, Korea,

The Canberra Hospital, Haematology, Canberra,

Australia,

BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA,

Inc., Hematology, San Mateo, USA,

Monash Health, Monash University,

Haematology, Clayton, Australia

Introduction: Zanubrutinib is a potent, speciﬁc next‐generation BTK

inhibitor with high selectivity for BTK vs the TEC‐and EGFR‐family

kinases, which may be related to off‐target toxicities.

Methods: This is a single‐arm, multicenter study of adults with R/R

MZL who previously received ≥1 prior therapy including ≥1 CD20

antibody regimen. All received zanubrutinib 160 mg bid until disease

progression/unacceptable toxicity. Primary endpoint was overall

response rate (ORR) by independent review committee (IRC). Sec-

ondary endpoints include investigator‐assessed (INV) ORR, duration

of response (DOR), progression‐free survival (PFS), and safety.

Results: By January 11, 2021, 68 patients (pts) were enrolled and

treated. Median age was 70 years (range, 37‐95). Subtypes included

extranodal (38%), nodal (38%), splenic (18%), and indeterminate in

6% of pts. Median number of prior therapies was 2 (range, 1‐6), and

32% had disease refractory to last therapy.

Median duration of drug exposure was 59.1 weeks (range, 3.7‐

84.1). At a median follow‐up of 15.5 months (range, 1.6‐21.7), INV ORR

was 74% with a CR rate of 24%. Responses were observed in all sub-

types. Median DOR and PFS were not reached. IRC review is ongoing.

Twenty‐eight (41%) pts discontinued treatment. The most com-

mon treatment‐emergent AEs reported in ≥10% of pts were diarrhea

(22%), bruising (21%), and constipation (15%). Neutropenia was the

most common grade ≥3 AE (10%). All‐grade AEs of interest included

neutropenia (13%), thrombocytopenia (13%), atrial ﬁbrillation/ﬂutter

(3%), and hypertension (3%). No major/serious hemorrhage was re-

ported. No AEs led to dose reductions.

Conclusions: Zanubrutinib demonstrated high response rates and

durable disease control with a favorable safety proﬁle in pts with R/R

MZL.

EA – previously submitted to EHA 2021.

The research was funded by: BeiGene (Beijing) Co., Ltd., Beijing,

China and BeiGene USA, Inc., San Mateo, CA, USA

Keywords: Indolent non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

J. Trotman

Research funding: BeiGene, Celgene, Roche, Takeda, PCYC, Janssen

164

SUPPLEMENT ABSTRACTS

A. Tedeschi

Consultant or advisory role: AbbVie, AstraZeneca, Janssen, BeiGene

Other remuneration: Speakers' Bureau: AbbVie, AstraZeneca, Jans-

sen, BeiGene

K. Linton

Consultant or advisory role: BeiGene, Celgene, Gilead, Karyopharm,

Roche, Takeda

Honoraria: Roche

Research funding: Genmab, BeiGene, Pharmacyclics, Roche

Educational grants: Bristol Meyers Squibb, Roche, Janssen, Celgene

P. McKay

Consultant or advisory role: Celgene, Janssen, BeiGene, Kite

Honoraria: Roche, Recordati

B. Hu

Consultant or advisory role: Kite, Cellectar

Research funding: Roche/Genetech, Celgene, BeiGene

H. Chan

Consultant or advisory role: Eusa, AbbVie, Janssen

Research funding: Janssen

P. L. Zinzani

Consultant or advisory role: Verastem, Celltrion, Gilead, Janssen‐

Cilag, Bristol Meyers Squibb, Sanoﬁ, Servier, Sandoz, MSD, TG

Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, ADC

Therapeutics

Other remuneration: Speakers' Bureau: Verastem, Celltrion, Gilead,

Janssen‐Cilag, Bristol Meyers Squibb, Servier, MSD, TG Therapeutics,

Takeda, Roche, Eusapharma, Kyowa Kirin

M. Coleman

Research funding: AbbVie, Pharmacyclics, AstraZeneca, Bristol

Meyers Squibb, Celgene

P. Browett

Consultant or advisory role: MSD, Janseen‐Cilag

Honoraria: Janssen, Roche

Research funding: Roche, Shire

R. Marcus

Consultant or advisory role: MEI Pharma

C. Portell

Consultant or advisory role: BeiGene, Genentech, Janssen, Kite/

Gilead, Morphosys, Pharmacyclics

Research funding: AbbVie, Genentech, Xencor, Inﬁnity, TG Thera-

peutics, Acerta, Kite, AstraZeneca, SeaGen, VelosBio

C. Thieblemont

Consultant or advisory role: Janssen, Novartis, Gilead, Roche, Cel-

gene/Bristol Myers Squibb

TABLE

SUPPLEMENT ABSTRACTS

165

Honoraria: Janssen, Novartis, Gilead, Roche, Celgene/Bristol Myers

Squibb

Educational grants: Roche, Gilead, Celgene, Bristol Myers Squibb,

Novartis

A. M. Liberati

Consultant or advisory role: Amgen, Servier, Celgene

Research funding: Novartis, Janssen, AbbVie, Roche, Amgen,

Celgene, Bristol Meyers Squibb, Takeda, Incyte, Pﬁzer, BeiGene,

Oncopeptides, AB, Verastem, Karyopharm, Archiegn, CTI Biopharma

Corp, Debiopharm International, Morphosys, Fribrogen, Onconova

Therapeutics Inc.

Educational grants: Roche, Takeda, AbbVie, Novartis, Sanophy Gen-

zyme, Verastem, Bristol Meyers Squibb

F. Cavallo

Consultant or advisory role: Roche

Honoraria: Janssen, Celgene, Gilead

Educational grants: Amgen

S. Iyengar

Consultant or advisory role: Takeda, Gilead, BeiGene

Educational grants: Takeda, Janssen

Other remuneration: Speakers' Bureau: Takeda, Gilead, AbbVie,

Janssen

R. Marasca

Honoraria: AbbVie

D. Talaulikar

Consultant or advisory role: Roche, EUSA pharma, George Clinical

Research funding: Roche

Educational grants: Roche

Other remuneration: Speakers' Bureau: Roche

M. Co

Employment or leadership position: BeiGene

Stock ownership: BeiGene

W. Zhou

Employment or leadership position: BeiGene

Stock ownership: BeiGene

J. Huang

Employment or leadership position: BeiGene

Stock ownership: BeiGene

Educational grants: BeiGene

Other remuneration: Patents, Royalties, OtherIntellectual Property:

BeiGene

S. Opat

Consultant or advisory role: Roche, Janssen, AbbVie, Celgene,

Takeda, Merck, Gilead, Mundipharma, AstraZeneca, CSL

Honoraria: Roche, Janssen, AbbVie, Celgene, Takeda, Merck, Gilead,

AstraZeneca

Research funding: BeiGene, Roche, Janssen, AbbVie, Takeda, Merck,

Gilead, Epizyme, AstraZeneca

Educational grants: Roche

108 |LONG TERM OUTCOMES OF GASTRIC MALT

LYMPHOMA TREATED WITH RADIOTHERAPY: A MULTI‐CENTRE

RETROSPECTIVE STUDY

C. Smith

, S. A. Gupta

, Y. S Chin

, S. R Thompson

Prince of Wales Hospital, Department of Radiation Oncology, Randwick,

Australia,

Calvary Mater Hospital, Department of Radiation Oncology,

Newcastle, Australia,

St George Hospital, Department of Radiation

Oncology, Kogarah, Australia

Introduction: Gastric mucosa‐associated lymphoid tissue (MALT)

lymphoma is a rare disease. Treatment has evolved over time, how-

ever radiotherapy remains an important deﬁnitive modality. We

assessed the long term outcomes of patients treated with early stage

gastric MALT marginal zone (MZ) lymphoma treated with deﬁnitive

radiotherapy at three Australian institutions.

Methods: We conducted a retrospective, multi‐centre study of pa-

tients with gastric MALT MZ lymphoma treated with radiotherapy

between 01/03/1999 and 29/05/2020. Eligible patients were: age ≥18

years, treated with curative intent radiotherapy, pathological diagnosis

of MALT MZ lymphoma. Time‐to‐event outcomes were calculated

from day 1 of radiotherapy. Toxicities were graded as per CTCAEv4.0.

Results: There were 33 eligible patients. Median age was 64 (range

37 – 82). 31 (94%) patients had Lugano stage I disease, 2 (6%) were

stage II. 20 (61%) patients previously received treatment (16 H. Py-

lori eradication (HPE), 2 chemotherapy, 1 surgery, and 1 HPE +

chemotherapy). Median prescribed RT dose was 30Gy (range 20 –

42) in 15 fractions (range 10 ‐28).

Complete response (CR) was reported in 30/31 (96.7%) of

endoscopically assessed cases. During median follow up of 66.2

months (IQR 22‐119 months), estimated 5 and 10 year local relapse

free survival (LRFS) were 92.6% (95% CI: 83‐100) and 92.6% (95%

CI: 83‐100); distant relapse free survival (DRFS) 95.8% (95%CI 88.2‐

100) and 64.7% (95%CI 43.4‐96.4); freedom from treatment failure

(FFTF) 92.6% (95%CI; 83.1‐100) and 62.5% (95%CI; 41.7‐93.7); and

progression free survival (PFS) 89.3% (95%CI; 78.4‐100) and 50.2%

(95%CI; 29.1‐86.6), respectively. There were 6 documented re-

currences; one local, four distant, and both in one patient; two cases

were high grade recurrences. Radiotherapy dose (<30 vs ≥30Gy),

previous H pylori eradication, or previous treatment failure were not

associated with inferior LRFS, DRFS or PFS on multivariate analysis.

5 and 10 year OS were 92.4% and 73.5% respectively. There were 2

acute grade 3 toxicities (1 anorexia, 1 fatigue) and no severe late

toxicities or treatment related deaths.

Conclusions: Patients with gastric MALT lymphoma treated with

deﬁnitive radiotherapy have excellent outcomes in terms of both local

control and survival. A signiﬁcant proportion in long term follow up

developed distant low grade disease, either relapsed or new primary

MZL. Extended follow up should be considered in these patients.

Treatment is well tolerated with minimal toxicity. Radiotherapy re-

mains an important modality in the treatment of this disease.

Keywords: Indolent non‐Hodgkin lymphoma Radiation Therapy

No conﬂicts of interest pertinent to the abstract.

166

SUPPLEMENT ABSTRACTS

109 |CHARACTERISTICS OF PATIENTS ACHIEVING COMPLETE

OR PARTIAL RESPONSE (CR/PR) WITH TAZEMETOSTAT (TAZ) IN

WILD‐TYPE RELAPSED/REFRACTORY (R/R) FOLLICULAR

LYMPHOMA (FL)

C. L. Batlevi

, G. Salles

, H. Tilly

, A. Chaidos

, P. McKay

, T. Phillips

S. Assouline

, P. Campbell

, V. Ribrag

, G. Laurent Damaj

, M.

Dickinson

, W. Jurczak

, M. Kaźmierczak

, S. Opat

, J. R.

Radford

, A. Schmitt

, A. Rajarethinam

, G. Shang

F. Morschhauser

Memorial Sloan Kettering Cancer Center, Lymphoma Service, Department

of Medicine, New York, USA,

Lyon‐Sud Hospital, University of Lyon, He-

matology, Pierre‐Bénite, France,

Centre Henri Becquerel and Rouen Uni-

versity, Department of Haematology and INSERM U1245, Rouen, France,

Imperial College Healthcare NHS Trust, Hammersmith Hospital, Depart-

ment of Medicine, London, UK,

Beatson West of Scotland Cancer Centre,

Department of Hematology, Glasgow, UK,

University of Michigan, Hema-

tology and Oncology, Ann Arbor, USA,

Division of Hematology, Sir Mor-

timer B. Davis‐Jewish General Hospital, Oncology, Montreal, Canada,

Barwon Health, University Hospital Geelong, Department of Clinical

Haematology, Geelong, Australia,

Gustave Roussy, Hematology, Villejuif,

France,

Hematology Institute University Hospital School of Medicine,

Hematology, Caen, France,

Peter MacCallum Cancer Centre, Royal Mel-

bourne Hospital, Department of Clinical Haematology, Melbourne,

Australia,

Maria Sklodowska‐Curie National Research Institute of

Oncology, Department of Hematology, Kraków, Poland,

Poznań Univer-

sity of Medical Sciences, Department of Hematology and Bone Marrow

Transplantation, Poznań, Poland,

Monash University, Department of

Haematology, Victoria, Australia,

University of Manchester, NIHR Man-

chester Clinical Research Facility, Manchester Academic Health Science

Centre, The Christie NHS Foundation Trust,, Department of Medical

Oncology, Manchester, UK,

Institut Bergonié, Department of Hematology,

Bordeaux, France,

Epizyme, Inc., Clinical Data Management, Cambridge,

USA,

Epizyme, Inc., Medical Affairs , Cambridge , USA,

Groupe de

Recherche sur les formes Injectables et les Technologies Associées, CHU de

Lille, Université de Lille, Oncology, Lille, France

Introduction: Enhancer of zeste homolog 2 (EZH2) epigenetic modiﬁer

expressed within germinal centers is an important regulator of FL

growth and survival. TAZ is an EZH2 inhibitor approved for R/R FL with

heightened overall response rates (ORRs) in mutant (MT) EZH2 but

similar progression‐free survival (PFS) in wild‐type (WT) and MT EZH2

cohorts. Pivotal phase 2 study identiﬁed ORRs (CR/PR) of 35% (19/54)

and 69% (31/45) in WT and MT EZH2 cohorts, respectively; PFS was

11.1 mo in WT and 13.8 mo in MT EZH2 cohorts. This exploratory

analysis assessed if baseline demographics or disease characteristics

correlate with response to TAZ in the WT EZH2 FL cohort.

Methods: Detailed methods of this open‐label multicenter phase

2 study (NCT01897571) are described in Morchhauser et al. Lancet

Oncol 2020. Oral TAZ 800 mg twice daily was assessed in adults with FL

after ≥2 prior systemic therapies. Baseline demographics and disease

characteristics were summarized using descriptive statistics.

Results: Of 99 patients (pts) with WT or MT EZH2, 19 pts with WT

EZH2 who received a median of 3 prior lines of therapy responded (2

CR, 17 PR). In general, WT EZH2 group had more pts with high‐risk

features than the MT EZH2 group. Baseline characteristics of pts in

the WT EZH2 group who achieved a response were similar to pts with

MT EZH2 who responded, as well as the general population (Table).

The number of pts with high‐risk features, such as progression of

disease within 24 mos (POD24), refractory to rituximab‐containing

regimen, and double refractory, were similar in the WT and MT

EZH2 responder groups, respectively. Pts with refractoriness to last

therapy represented 26.3% and 51.6% of WT and MT EZH2 re-

sponders, but the populations were small.

Conclusions: Characteristics of responders in the WT EZH2 FL cohort

were reﬂective of the overall population, with a broad distribution of

disease severity at baseline. Responders with WT EZH2 included pts

with high‐risk features, such as POD24, refractoriness to rituximab‐

based regimens, or double refractory disease. Response to TAZ in pts

with WT EZH2 R/R FL appears to be independent of baseline clinical

factors; however, small numbers preclude a deﬁnitive assessment.

Additional correlative molecular analyses are in progress.

The research was funded by: Epizyme, Inc.

Keywords: Indolent non‐Hodgkin lymphoma, Therapeutics and Clin-

ical Trials in Lymphoma ‐Other

Conﬂicts of interests pertinent to the abstract

C. L. Batlevi

Consultant or advisory role: Life Sci, GLG, Juno/Celgene, Seattle

Genetics, Kite, Karyopharm, TG Therapeutics

Stock ownership: None over $10,000 not including potential holdings

in retirement mutual funds

Honoraria: Dava Oncology

TABLE: Baseline Disease Characteristics of Responders

SUPPLEMENT ABSTRACTS

167

Research funding: Janssen, Novartis, Epizyme, Xynomics, Bayer,

Autolus, Roche

G. Salles

Consultant or advisory role: Abbvie, Autolus, Bristol Myers Squibb,

Celgene, Debiopharm, Genmab, Gilead, F. Hoffmann‐La Roche, Epi-

zyme, Janssen, Karyopharm, Kite Pharma, and Takeda, and has

participated in educational events for Abbie, Amgen, Celgene, Gilead,

and Janssen

Honoraria: Abbvie, Autolus, Bristol Myers Squibb, Celgene, Debio-

pharm, Genmab, Gilead, F. Hoffmann‐La Roche, Epizyme, Janssen,

Karyopharm, Kite Pharma, and Takeda, and has participated

in educational events for Abbie, Amgen, Celgene, Gilead, and Janssen

H. Tilly

Consultant or advisory role: AstraZeneca; Karyopharm Therapeutics;

Roche

Honoraria: Celgene; Roche/Genentech; SERVIER

Research funding: Celgene (Inst)

Educational grants: Roche

P. McKay

Consultant or advisory role: BeiGene, Celgene, Gilead, Janssen,

Roche, and Takeda

Educational grants: Janssen and Takeda

Other remuneration: Fees for lectures and Speakers bureau Gilead,

Janssen, Roche, and Takeda

T. Phillips

Consultant or advisory role: AbbVie, AstraZeneca, Bayer, BeiGene,

Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Phar-

macyclics, and Seattle Genetics

Research funding: AbbVie and Bayer

Educational grants: Incyte

S. Assouline

Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, F.

Hoffmann‐La Roche, Janssen, and Pﬁzer Inc

Honoraria: AbbVie, AstraZeneca, BeiGene, F. Hoffmann‐La Roche,

Janssen, and Pﬁzer Inc

Research funding: BeiGene, F. Hoffmann‐La Roche, and Takeda

Other remuneration: Speakers Bureau: AbbVie, AstraZeneca, and

Janssen

P. Campbell

Consultant or advisory role: Amgen, AstraZeneca, CSL Behring,

Janssen, Novartis, and Roche

Stock ownership: argenX and Epizyme

Research funding: Amgen, Celgene (BMS), Janssen, Novartis, and

Roche

V. Ribrag

Consultant or advisory role: Bristol Myers Squibb, Epizyme, Immune

Design, Incyte, Inﬁnity, MSD, Nanostring, Pharmamar, Roche/Gen-

entech, Servier, AstraZeneca, Epizyme, F. Hoffmann‐La Roche, Gilead,

Stock ownership: argenX and Epizyme

Research funding: arGEN‐X‐BVBA, argenX, and Epizyme

G. Laurent Damaj

Consultant or advisory role: Accord, Iqone, Roche, and Takeda

Honoraria: Accord, Roche, and Takeda

Educational grants: AbbVie, Pﬁzer, Roche, and Takeda

M. Dickinson

Consultant or advisory role: Gilead, Janssen, Merck Sharp & Dohme,

Novartis, and Roche

Honoraria: Gilead, Janssen, Novartis, and Roche

Research funding: Gilead and Novartis

Other remuneration: speakers’ bureaus for board of directors for

Gilead, Janssen, Novartis, and Roche

W. Jurczak

Consultant or advisory role: Acerta, Aﬁmed, AstraZeneca, BeiGene,

Epizyme, European Medicines Agency, Janssen, Sanoﬁ‐Novartis

Research funding: Acerta, Bayer, BeiGene, Celgene, Gilead, Janssen

China, MEI Pharma, Merck, MorphoSys, Nordic Nanovecotr, Phar-

macyclics, Roche, Servier, Takeda, and TG Therapeutics

M. Kaźmierczak

Consultant or advisory role: Acerta, Aﬁmed, AstraZeneca, Bei-

Gene, Epizyme, European Medicines Agency, Janssen, Sanoﬁ‐

Novartis

Research funding: Acerta, Bayer, BeiGene, Celgene, Gilead, Janssen

China, MEI Pharma, Merck, MorphoSys, Nordic Nanovecotr, Phar-

macyclics, Roche, Servier, Takeda, and TG Therapeutics

S. Opat

Consultant or advisory role: AbbVie, CSL, F. Hoffman‐La Roche,

Gilead, Janssen, Merck, and Mundipharma

Honoraria: AbbVie, AstraZeneca, Celgene, CSL, Gilead, Janssen,

Merck, Mundipharma, Roche, and Takeda

Other remuneration: advisory board or board of directors for Abb-

Vie, AstraZeneca, Celgene, CSL, Gilead, Janssen, Merck, Mundi-

pharma, Roche, and Takeda

J. R. Radford

Consultant or advisory role: Bristol Myers Squibb, Kite Pharma,

Novartis, and Takeda

Stock ownership: AstraZeneca and GlaxoSmithKline

Research funding: ADCT, Pﬁzer, and Takeda

Other remuneration: speakers’ bureau or board of directors for

ADCT, Bristol Myers Squibb, Seattle Genetics, and Takeda

A. Schmitt

Consultant or advisory role: advisory board or board of directors for

Celgene

Honoraria: Janssen and Roche

A. Rajarethinam

Employment or leadership position: Epizyme, Inc.

Stock ownership: Epizyme, Inc.

G. Shang

Employment or leadership position: Medivation, Pﬁzer, Epizyme, Inc.

Stock ownership: Epizyme, Inc.

168

SUPPLEMENT ABSTRACTS

F. Morschhauser

Consultant or advisory role: F. Hoffmann‐La Roche, Genentech,

Servier, AbbVie, Celgene, Epizyme, and Gilead

Honoraria: Janssen

110 |ATEZOLIZUMAB +OBINUTUZUMAB +VENETOCLAX IN

PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR

LYMPHOMA: PRIMARY ANALYSIS OF A PHASE 2 TRIAL FROM

LYSA

G. Cartron

, E. Bachy

, S. Guidez

, E. Gyan

, R. Gressin

, N.

Morineau

, D. Sibon

, O. Casasnovas

, S. Le Gouill

, H. Tilly

, L.

Ysebaert

, J. M. Schiano de Colella

, P. Feugier

, E. Nicolas

Virelizier

, C. Haioun

, G. Damaj

, K. Tarte

, C. Laurent

, R.

Houot

, C. Thieblemont

, F. Morschhauser

, C. Herbaux

CHU Montpellier, Hématologie Clinique, Montpellier, France,

CHU,

Hematology, Lyon, France,

CHU, Hematology, Poitiers, France,

CHU,

Hematology, Tours, France,

CHU, Hematology, Grenoble, France,

CHD

Vendée, Hematology, La Roche sur Yon, France,

Necker, Hematology,

Paris, France,

CHU, Hematology, Dijon, France,

CHU, Hematology,

Nantes, France,

CHB Unicancer, Hematology, Rouen, France,

Oncopole, Hematology, Toulouse, France,

IPC, Hematology, Marseille,

France,

CHU, Hematology, Nancy, France,

CLB, Hematology, Lyon,

France,

Mondor, Hematology, Paris, France,

CHU, Hematology, Caen,

France,

CHU, Pathology, Rennes, France,

Oncopole, Pathology,

Toulouse, France,

CHU, Hematology, Rennes, France,

St Louis,

Hematology, Paris, France,

CHU, Hematology, Lille, France

Introduction: Relapsed and refractory (R/R) Follicular Lymphoma (FL)

treatment remains challenging. Atezolizumab (ATE) and obinutuzumab

(OBI) are monoclonal antibodies acting respectively to inhibit T‐

lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity,

whereas venetoclax (VEN) is a small molecule inhibiting BCL‐2.

Combining tumor‐targeted therapies with agents that enhance anti‐

tumor immunity represents an attractive treatment paradigm. This

LYSA sponsored multicenter phase 2 trial (NCT03276468) evaluated

ATE, OBI and VEN combination in R/R B‐cell lymphomas. Herein, we

present primary efﬁcacy and safety data from the FL cohort.

Methods: Patients ≥18 years with biopsy‐conﬁrmed R/R FL who

failed at least one line of therapy were eligible. OBI was given IV at 1

g on day (D) 1, 8 and 15 of cycle (C) 1 and on D1 from C2 to C8 every

3 weeks. ATE was given IV, 1.2 g every 3 weeks, started at D2 of C1,

then administered at D2 of each cycle for 24 cycles. VEN was given

orally at 800 mg/D at full dose, starting on D8C1 for 24 cycles. The

primary endpoint was the Overall Response Rate (ORR) evaluated by

Lugano criteria at the end of induction (EOI) after 8 cycles of ATE,

OBI and VEN (M6) or at premature treatment discontinuation.

Results: At the time of the primary analysis (08 Jan 2021), 58 FL

patients were enrolled. The median follow‐up was 14.5 months, 45

patients completed induction phase and 34 patients started main-

tenance. Baseline characteristics were: median age, 56 years (38‐83);

male, 66.1%; Ann Arbor Stage III/IV, 85.7%; FLIPI HR, 47.3%; >2

prior lines of therapy, 32.1%; refractory to last line of prior regimen,

26.8%; and exposed to ASCT, 30.4%. The OMRR at EOI was

measured at 53.6% [41.8%‐65.1%], including 30.4% of CMR whereas

OMRR at C4 was 75.0% [61.6%‐85.6%], including 28.6% of CMR.

Best of Response Rate (BOR) was 80.4% [69.6%‐88.6%] including

35.7% of CMR. To date, 23 patients relapsed after an initial response

(51% of the 45 responders). Thirty‐seven patients (63%) received the

full induction treatment. At the time of analysis, a median of 8 cycles

[1‐8] has been administered. A total of 41 (70.7%) patients experi-

enced grade 3–4 adverse event (AE) and 1 had an AE that led to

discontinuation of any drug. AE of grade 3 or more reported in at

least 10% of patients were neutropenia (41.4%), thrombocytopenia

(24.1%) and lymphopenia (22.4%). Of note, two patients experienced

autoimmune colitis (grade 2 and 3) and one patient experience a

grade 2 immune‐related pancreatitis during induction.

Conclusion: ATE, OBI and VEN combo appears to be well tolerated,

with no unexpected toxicity brought by the combination. The ORR at

EOI seems to be comparable to other innovative regiments in this

setting, with durable responses to date.

The research was funded by: Roche, Abbvie

Keywords: Indolent non‐Hodgkin lymphoma, Combination Therapies,

Immunotherapy

No conﬂicts of interest pertinent to the abstract.

111 |POLATUZUMAB VEDOTIN +OBINUTUZUMAB +

VENETOCLAX IN PATIENTS WITH RELAPSED/REFRACTORY (R/R)

FOLLICULAR LYMPHOMA (FL): PRIMARY ANALYSIS OF A PHASE

1B/2 TRIAL

R. Bannerji

, S. Yuen

, T. Phillips

, C. Arthur

, I. Isuﬁ

, P. Marlton

, J.

F. Seymour

, P. Corradini

, A. Molinari

, G. Gritti

, R. Emmons

, J.

Hirata

, L. Musick

, S. Saha

, B. Croft

, C. Flowers

Rutgers Cancer Institute of New Jersey, Section of Hematologic

Malignancies, New Brunswick, New Jersey, USA,

The Calvary Mater

Newcastle Hospital, Waratah, Australia,

University of Michigan Medical

School, Division of Hematology and Oncology, Ann Arbor, USA,

Royal

North Shore Hospital, Sydney, Australia,

Yale University, Smilow Cancer

Hospital, Section of Hematology, New Haven, USA,

Princess Alexandra

Hospital and University of Queensland, Department of Haematology,

Brisbane, Australia,

Peter MacCallum Cancer Centre & Royal Melbourne

Hospital, Department of Haematology, Melbourne, Australia,

University of

Milan, Istituto Nazionale dei Tumori, Medical Oncology and Hematology

Department, Milan, Italy,

AUSL Romagna, Ospedale degli Inﬁrmi, Dirigente

Medico Ematologia, Rimini, Italy,

ASST Papa Giovanni XXIII, UOC

Ematologia, Bergamo, Italy,

James Graham Brown Cancer Center,

Louisville, USA,

Genentech, Inc., Product Development Oncology, South

San Francisco, USA,

F. Hoffmann‐La Roche Ltd, Product Development

Biometrics, Welwyn Garden City, UK,

M.D. Anderson Cancer Center,

Department of Lymphoma/Myeloma, Houston, USA

SUPPLEMENT ABSTRACTS

169

Introduction: Polatuzumab vedotin (Pola) +obinutuzumab (G)

demonstrated activity and tolerability in a Phase 1b/2 trial of patients

(pts) with R/R FL (Phillips, et al. Blood 2016). Preclinical studies with

venetoclax (Ven) showed that concurrent treatment with Pola pro-

motes MCL‐1 degradation, a known mechanism of resistance to Ven,

and enhances in vivo anti‐tumor efﬁcacy (Amin, et al. AACR 2020).

Here, we report the primary safety/efﬁcacy analysis with Pola‐G‐Ven

in a Phase 1b/2 study of pts with R/R FL (GO29833; NCT02611323).

Methods: Pts received induction treatment every 21 days (D) x six

cycles (C) of: Pola 1.4–1.8mg/kg intravenously (IV) in dose esca-

lation (DE) or recommended Phase II dose (RP2D) on D1; G

1000mg IV (C1: D1, D8, D15; C2–6: D1); and oral Ven 200–

800mg (DE or RP2D; D1–21). Pts with complete response/partial

response/stable disease (CR/PR/SD) at end of induction (EOI)

received maintenance with G (1000mg on D1 every 2 months [mo]

for 24 mo) and Ven (200–800mg daily) for 8 mo. Primary end-

points were safety/tolerability and positron emission tomography

(PET)‐CR rate at EOI by independent review committee (IRC) us-

ing modiﬁed Lugano criteria.

Results: At the primary analysis (Oct 05, 2020), 74 pts were enrolled.

Median pt age was 64 years (range 36–78); male (57%); Ann Arbor

Stage III–IV (86%); FL International Prognostic Index high risk ≥3

(55%); bulky disease ≥7cm (16%); prior lines of therapy ≥2 (74%);

refractory to: last prior therapy (51%), any prior anti‐CD20 therapy

(55%), both anti‐CD20 therapy and an alkylating agent (double re-

fractory; 55%). Grade 3–4 adverse events (AEs) were experienced by

73% of pts; most commonly, neutropenia (39%), thrombocytopenia

(19%), and infections (16%; mainly pneumonia). AEs led to dose

reduction in 38% and interruption in 68% of pts (mainly modiﬁcations

to Ven). One fatal AE was reported (pneumonia). In total, 49 pts were

treated at RP2D (Pola 1.8mg/kg +Ven 800mg) and were evaluable

for efﬁcacy. PET‐CR rate at EOI by IRC was 57% (Table). With a

median follow‐up of 14.4 mo (range 8.2–28.4), the 12‐mo

progression‐free survival (PFS) was 73% (95% conﬁdence interval:

59.4–86.9). Median PFS was not reached.

Conclusions: The safety proﬁle of Pola‐G‐Ven is consistent with the

known proﬁles of the individual drugs. Response rates at EOI with

Pola‐G‐Ven are encouraging in this R/R FL patient population.

Additional follow‐up is needed to assess PFS beneﬁt during mainte-

nance treatment and beyond.

EA – previously submitted to ASCO 2021.

The research was funded by: F. Hoffmann‐La Roche Ltd/Genentech,

Inc. Third party medical writing assistance, under the direction of the

authors, was provided by Carla Smith, MSc, of Ashﬁeld MedComms,

an Ashﬁeld Health company, and was funded by F. Hoffmann‐La

Roche Ltd.

Keywords: Indolent non‐Hodgkin lymphoma, Molecular Targeted

Therapies, Combination Therapies

Conﬂicts of interests pertinent to the abstract

R. Bannerji

Employment or leadership position: Sanoﬁ Pasteur

Research funding: Abbvie, Genentech, Inc., F. Hoffmann‐La Roche

Ltd, Regeneron, Abbvie/Pharmacyclics

S. Yuen

Educational grants: Genentech, Inc.

T. Phillips

Consultant or advisory role: ADCT, Genentech, Inc., Abbvie, Phar-

macyclics, Bayer, BMS, Incyte, TG Therapeutics, Gilead, Astra Zeneca

Honoraria: Lymphoma connect

Research funding: Bayer, Abbvie, BMS, Incyte

I. Isuﬁ

Consultant or advisory role: Astra Zeneca, Celgene, Kite, Novartis,

Epizyme

Honoraria: Bayer Taiwan

P. Marlton

Consultant or advisory role: F. Hoffmann‐La Roche Ltd, AbbVie,

Janssen, Astellas, Gilead, AstraZeneca, BeiGene, Jazz Pahrmaceuticals

Educational grants: F. Hoffmann‐La Roche Ltd

Other remuneration: Speakers' bureau: AbbVie

TABLE: Responses at EOI by modiﬁed Lugano criteria (RP2D; =49)

170

SUPPLEMENT ABSTRACTS

J. F Seymour

Consultant or advisory role: Abbvie, Acerta Pharma, Janssen, F.

Hoffmann‐La Roche Ltd, Sunesis Pharmaceuticals, Takeda, AstraZe-

neca, Bristol‐Myers Squibb, Gilead Sciences, MEI Pharma, MorphoSys

Honoraria: Abbvie, Acerta Pharma, Janssen, F. Hoffmann‐La Roche

Ltd, Sunesis Pharmaceuticals, Takeda

Research funding: Abbvie, Celgene, Janssen, F. Hoffmann‐La

Roche Ltd

Educational grants: Abbvie, F. Hoffmann‐La Roche Ltd

Other remuneration: Speakers' bureau: Abbvie, F. Hoffmann‐La

Roche Ltd; Expert Testimony: F. Hoffmann‐La Roche Ltd

P. Corradini

Consultant or advisory role: AbbVie, ADC Therapeutics, Amgen,

Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin,

Novartis, F. Hoffmann‐La Roche Ltd, Sanoﬁ, Servier, Takeda

Honoraria: AbbVie, ADC Therapeutics, Amgen, Celgene, Daii-

chi Sankyo, Gilead, Incyte, Janssen, Jazz Pharmaceutics, Kite,

KyowaKirin, Novartis, F. Hoffmann‐La Roche Ltd, Sanoﬁ, Servier,

Takeda

G. Gritti

Consultant or advisory role: Autolus, Gilead, IQvia, Amgen, F.

Hoffmann‐La Roche Ltd, Takeda

Honoraria: Takeda

Educational grants: F. Hoffmann‐La Roche Ltd, AbbVie, Gilead,

Janssen, Takeda

J. Hirata

Employment or leadership position: Genentech, Inc.

Stock ownership: F. Hoffmann‐La Roche Ltd

L. Musick

Employment or leadership position: Genentech, Inc.

Stock ownership: F. Hoffmann‐La Roche Ltd/GNE

S. Saha

Employment or leadership position: Genentech, Inc.

B. Croft

Employment or leadership position: Genentech, Inc.

Stock ownership: Genentech, Inc./F. Hoffmann‐La Roche Ltd

C. Flowers

Consultant or advisory role: Abbvie, Bayer, BeiGene, Celgene,

Denovo Biopharma, Genentech/Roche, Gilead, Karyopharm, Phar-

macyclics/Janssen, Spectrum

Research funding: 4D, Abbvie, Acerta, Adaptimmune, Allogene,

Amgen, Bayer, Celgene, Cellectis, EMD, Gilead, Genentech/Roche,

Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar,

Novartis, Pﬁzer, Pharmacyclics, Sanoﬁ, Takeda, TG Therapeutics,

Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative

Oncology Group, National Cancer Institute, V Foundation, Cancer

Prevention and Research Institute of Texas: CPRIT Scholar in Cancer

Research

112 |CHRONOS‐3: RANDOMIZED PHASE III STUDY OF

COPANLISIB PLUS RITUXIMAB VS RITUXIMAB/PLACEBO IN

RELAPSED INDOLENT NON‐HODGKIN LYMPHOMA (INHL)

P. L. Zinzani

, M. Capra

, M. Özcan

, F. Lv

, W. Li

, E. Yañez

, K.

Sapunarova

, T. Lin

, J. Jin

, W. Jurczak

, A. Hamed

, M.‐C. Wang

R. Baker

, I. Bondarenko

, Q. Zhang

, J. Feng

, K. Geissler

, M.

Lazaroiu

, G. Saydam

, Á. Szomor

, K. Bouabdallah

, R. Galiulin

T. Uchida

, L. Mongay Soler

, A. Cao

, F. Hiemeyer

, A. Mehra

B. H. Childs

, Y. Shi

, M. J. Matasar

IRCCS Azienda Ospedaliero‐Universitaria di Bologna, Istituto di Emato-

logia “Seràgnoli”; Università di Bologna, Dipartimento di Medicina Spe-

cialistica, Diagnostica e Sperimentale, Bologna, Italy,

Hospital Mãe de

Deus, Centro de Hematologia e Oncologia, Porto Alegre, Brazil,

Ankara

University School of Medicine, Hematology Department, Ankara, Turkey,

Fudan University Shanghai Cancer Center, Department of Medical

Oncology, Shanghai, China,

The First Hospital of Jilin University,

Department of Hematology, Changchun, China,

University of La Fron-

tera, Department of Internal Medicine, Oncology‐Hematology Unit,

Temuco, Chile,

Medical University, Department of Internal Medicine,

Hematology Division, Plovdiv, Bulgaria,

Sun Yat‐sen University Cancer

Center, Department of Medical Oncology, Guangzhou, China,

The First

Afﬁliated Hospital of Zhejiang University College of Medicine, Department

of Hematology, Hangzhou, China,

Maria Skłodowska‐Curie National

Research Institute of Oncology, Department of Clinical Oncology, Krakow,

Poland,

Petz Aladár Megyei Oktató Kórház, Hematológiai Osztály, Gyor,

Hungary,

Chang Gung Memorial Hospital Kaohsiung, Department of

Medicine, Kaohsiung, Taiwan,

Perth Blood Institute, Murdoch Univer-

sity, Western Australia Centre for Thrombosis and Haemostasis, Perth,

Australia,

City Dnipropetrovsk Multi‐ﬁeld Clinical Hospital, 4 DSMA,

Chemotherapy Department, Dnipro, Ukraine,

Harbin Medical Univer-

sity, Cancer Hospital, Department of Medical Oncology, Harbin, China,

Jiangsu Cancer Hospital, Department of Medical Oncology, Nanjing,

China,

Sigmund Freud University, 5th Medical Department with He-

matology, Oncology and Palliative Medicine, Vienna, Austria,

S.C. Poli-

clinica de Diagnostic Rapid S.A., Department of Hematology, Brasov,

Romania,

Ege Üniversitesi Tıp Fakültesi, Division of Hematology, Izmir,

Turkey,

Pécsi Tudományegyetem Klinikai Központ, 1st Department of

Internal Medicine, Pécs, Hungary,

University Hospital of Bordeaux,

Hematology and Cellular Therapy Department, Bordeaux, France,

Clinical Oncological Dispensary of Omsk Region, Department of

Chemotherapy for Children and Adults, Omsk, Russian Federation,

Japanese Red Cross Nagoya Daini Hospital, Department of Hematology

and Oncology, Nagoya, Japan,

Bayer HealthCare Pharmaceuticals, Inc.,

Clinical Development, Whippany, USA,

Bayer HealthCare Pharmaceu-

ticals, Inc., Clinical Statistics, Whippany, USA,

Pharmaceuticals Division,

Bayer AG, Clinical Statistics, Berlin, Germany,

Bayer HealthCare Phar-

maceuticals, Inc., Clinical Development, Whippany, USA,

Bayer

HealthCare Pharmaceuticals, Inc., Clinical Development, Whippany, USA,

National Cancer Center/National Clinical Research Center for Cancer/

Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union

Medical College, Department of Medical Oncology, Beijing, China,

SUPPLEMENT ABSTRACTS

171

Memorial Sloan Kettering Cancer Center, Department of Medicine, New

York, USA

Introduction: Rituximab (R)‐based therapies are standard for pa-

tients (pts) with relapsed advanced iNHL. Copanlisib (C) is a PI3K

inhibitor approved as monotherapy for relapsed follicular lymphoma

(FL) in pts who have had ≥2 prior systemic therapies. We report

primary data from the Phase III CHRONOS‐3 study of treatment

with C+Rvs placebo (P)+R in relapsed iNHL (NCT02367040).

Methods: Pts with relapsed iNHL who were progression‐free and

treatment‐free for ≥12 months (mo) after last R‐based therapy or

unwilling/unﬁt to receive chemotherapy were randomized 2:1 to

receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15

(28‐day cycle); R 375 mg/m

was given i.v. on days 1, 8, 15, and 22

during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint:

centrally assessed progression‐free survival (PFS). Secondary end-

points: objective response rate (ORR), duration of response, complete

response rate (CRR), overall survival (OS), and treatment‐emergent

adverse events (TEAEs). The data cut‐off date was August 31, 2020.

Results: 307 pts were randomized to C+R and 151 to P+R. FL was

the most common lymphoma histology subtype (60.0%), followed by

marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and

lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM,

8.3%). Median age was 63 years (range 28‐91). With a median follow‐

up of 19.2 mo, the primary study endpoint was met: C+R signiﬁcantly

reduced the risk of disease progression/death vs P+R (hazard ratio

[HR] 0.52 [95% CI 0.39, 0.69]; 1‐sided p =0.000002); median PFS

was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5),

respectively. Reductions in risk of progression/death were seen

across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833];

MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443

[0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7%

(CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all

iNHL subtypes with C+R treatment. Median OS was not estimable.

Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were

hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]),

and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyper-

glycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]),

neutropenia (16.4%/12.3%), and upper respiratory tract infection

(16.4%/0%) were the most common TEAEs. Serious adverse events

were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in

6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment‐related;

pneumonitis) and 1 (0.7%) receiving P+R.

Conclusions: C+R demonstrated broad and superior efﬁcacy vs P+R

in pts with relapsed iNHL. The safety proﬁle of C+R was manageable

and consistent with C and R as monotherapy. Copanlisib is the ﬁrst

PI3K inhibitor to be safely combined with R in relapsed iNHL, rep-

resenting a potential new therapy option for relapsed iNHL across all

subtypes.

EA – previously submitted to AACR and EHA 2021.

The research was funded by: Bayer AG, Writing Support was pro-

vided by Complete HealthVizion

Keywords: Indolent non‐Hodgkin lymphoma, Combination Therapies

Conﬂicts of interests pertinent to the abstract

P. L. Zinzani

Consultant or advisory role: AbbVie, ADC Therapeutics, Bristol

Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune

Design, Incyte, Janssen, Janssen‐Cilag, Kyowa Kirin, Merck, MSD,

Portola, Roche, Sandoz, Sanoﬁ, Servier, Takeda, TG Therapeutics,

Verastem

Honoraria: AbbVie, ADC Therapeutics, Bristol Myers Squibb, EUSA

Pharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, MSD, Roche,

Servier, Takeda, TG Therapeutics, Verastem

Research funding: Portola

M. Özcan

Honoraria: Amgen and Takeda

Research funding: AbbVie, Archigen Biotech, Bayer, Celgene, F.

Hoffmann‐La Roche Ltd., Janssen, MSD, Takeda

Educational grants: AbbVie, Amgen, Bristol Myers Squibb, F.

Hoffmann‐La Roche Ltd., Janssen, Takeda

Other remuneration: Abdi İbrahim, Jazz Pharmaceuticals, Sanoﬁ

W. Jurczak

Research funding: Bayer, Gilead, MEI Pharma, TG Therapeutics

R. Baker

Consultant or advisory role: Janssen‐Cilag, Roche

Research funding: AbbVie, Acerta Pharma, Alexion, Amgen, Bayer,

Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CSL Behring,

Daiichi Sankyo, Janssen‐Cilag, MorphoSys AG, Pﬁzer, Portola, Rigel

Pharmaceuticals, Roche, Sanoﬁ, Takeda, Technoclone

K. Geissler

Consultant or advisory role: Amgen, Celgene, Novartis, Ratiopharm,

Roche

T. Uchida

Other remuneration: Bristol Myers Squibb, Celgene, Chugai Phar-

maceutical, Eisai, Janssen, Kyowa Kirin, Mundipharma, Nippon Shi-

nyaku, Novartis, Ono Pharmaceutical, Otsuka, Pﬁzer, Takeda

L. Mongay Soler

Employment or leadership position: Bayer HealthCare Pharmaceu-

ticals, Inc.

A. Cao

Employment or leadership position: Bayer HealthCare Pharmaceu-

ticals, Inc.

F. Hiemeyer

Employment or leadership position: Bayer AG

A. Mehra

Employment or leadership position: Bayer HealthCare Pharmaceu-

ticals, Inc.

B. H. Childs

Employment or leadership position: Bayer HealthCare Pharmaceu-

ticals, Inc.

172

SUPPLEMENT ABSTRACTS

M. J. Matasar

Consultant or advisory role: Bayer, Daiichi Sankyo, F. Hoffmann‐La

Roche Ltd., Genentech, Inc., Juno Therapeutics, Merck, Rocket Medi-

cal, Seattle Genetics, Takeda, Teva, ImmunoVaccine Technologies, TG

Therapeutics

Honoraria: Bayer, F. Hoffmann‐La Roche Ltd., Genentech, Inc.,

GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacy-

clics, Seattle Genetics, Takeda, TG Therapeutics

Research funding: Bayer, F. Hoffmann‐La Roche Ltd., Genentech, Inc.,

GlaxoSmithKline, Janssen, Pharmacyclics, Rocket Medical, Seattle

Genetics, IGM Biosciences

113 |ZANDELISIB, A PI3KδINHIBITOR ON INTERMITTENT

SCHEDULE (IS) IN FOLLICULAR LYMPHOMA PATIENTS WHO

PROGRESSED WITHIN 24 MONTHS OF FIRST‐LINE

CHEMOIMUNOTHERAPY (POD24)

J. Pagel

, N. Reddy

, D. Jagadeesh

, A. Stathis

, A. S. Asch

, H.

Salman

, V. P. Kenkre

, J. D. Soumerai

, J. Llorin‐Sangalang

, I. Gor-

batchevsky

, J. Li

, A. D. Zelenetz

Swedish Cancer Institute, Hematology and Oncology, Seattle,

Washington, USA,

Vanderbilt University Medical Center, Hematology

and Oncology, Nashville, USA,

Cleveland Clinic, Hematology and Medical

Oncology, Cleveland, USA,

IOSI‐Oncology Institute of Southern

Switzerland, Ospedale Regionale Di Bellinzona E Valli, Oncology, Bellin-

zona, Switzerland,

University of Oklahoma Health Sciences Center‐

Stephenson Cancer Center, Hematology and Oncology, Oklahoma City,

USA,

Stony Brook Medical Center, Hematology and Oncology, Stony

Brook, USA,

Carbone Cancer Center, Hematology and Oncology, Madi-

son, USA,

Massachusetts General Hospital, Hematology and Oncology,

Boston, USA,

MEI Pharma, Inc, Clinical Development, San Diego, USA,

MEI Pharma,

Inc, Biometrics, San Diego, USA,

Memorial Sloan Kettering Cancer

Center, Hematology and Oncology, New York City, USA

Introduction: Follicular lymphoma (FL) patients (pts) with POD24

have poorer survival and may beneﬁt from novel therapies at relapse.

Zandelisib (ME‐401), a potent, selective, and structurally differenti-

ated oral PI3kδinhibitor was evaluated in a dose escalation/expan-

sion Phase 1b study for FL demonstrating a high objective response

rate (ORR) and well tolerated when given on IS (J Clin Oncol

2020;38: #8016). We report here results based on POD24 status

(NCT02914938)

Methods: Eligible pts had ≥1 prior therapy, adequate bone marrow

and organ function, ECOG performance status ≤2, and no prior PI3K

therapy. Zandelisib was administered at 60 mg once daily for 8 weeks

followed by IS on days 1‐7 of each subsequent 28‐day cycle, either as

monotherapy or with rituximab at 375 mg/m

for 8 doses in Cycles 1‐

6. Treatment was continued until disease progression, intolerance, or

withdrawal of consent. Imaging scans were obtained after 2 and 6

cycles, and then every 6 cycles. Response was reported based on

Lugano criteria.

Results: 37 FL pts were enrolled and received zandelisib on IS as

monotherapy (N =18) or in combination with rituximab (N =19).

Median number of prior therapies =2 (range, 1‐5). The ORR was

86.5% (32/37) with 27% CR (complete response). The ORR and CR

rate were 77.8 % (14/18) and 27.8% in the monotherapy group and

94.7% (18/19) and 26.3% respectively in the rituximab combination

group. Median duration of response (DOR) among all pts was not

reached with a median follow‐up of 16.9 months (mos) (1.2‐33.1+).

22 pts (59%) were POD24, of which 15 (68%) had ≥2 prior lines of

therapy. Despite more refractory disease, ORR among the POD24

pts was 81.8% (Table). Zandelisib on IS was well tolerated. 3 pts (8%)

discontinued therapy due to an adverse event (AE). Grade (Gr) 3 AE

of special interest (AESI) were 2 (5.4%) diarrhea, 2 (5.4%) colitis, 3

(8.1%) rash, 3 (8.1%) ALT elevation, 1 (2.7%) AST elevation and no

pulmonary infection.

Conclusions: Zandelisib administered on IS as monotherapy or with

rituximab resulted in a high‐rate of durable responses in FL, both in

POD24 and non‐POD24 groups. Therapy was well‐tolerated with

low rate of Gr 3 class‐related AESI and discontinuation due to AE's.

Zandelisib as monotherapy is being evaluated in a global Phase 2

study in FL and MZL after failure of 2 prior therapies

(NCT03768505). A Phase 3 study of zandelisib plus rituximab in FL

and MZL after failure of prior immunochemotherapy will begin

enrollment in 2021.

EA – previously submitted to ASCO 2021.

The research was funded by: MEI Pharma

Keywords: Molecular Targeted Therapies, Indolent non‐Hodgkin

lymphoma

Conﬂicts of interests pertinent to the abstract

J. Pagel

Consultant or advisory role: Gilead Sciences, Actinium Pharmaceu-

ticals, BeiGene, Loxo, Astra Zeneca, MEI Pharma, MorphoSys

SUPPLEMENT ABSTRACTS

173

N. Reddy

Honoraria: Celgene, Morphosys

D. Jagadeesh

Consultant or advisory role: Atara Biotherapeutics, Verastem, Kyowa

Kirin

Research funding: Seattle Genetics, Regeneron, MEI Pharma,

Debiopharm Group, Seattle Genetics, Trillium THerapeutics, ADC

Therapeutics, Rhizen Pharmaceuticals

A. Stathis

Consultant or advisory role: Lilly, Bayer,

Research funding: Merck, Pﬁzer, Roche, Novartis, Bayer, Lilly, ADC

Therapeutics, MEI Pharma, Cellestia Biotech

Educational grants: PharmaMar, Abbvie

A. S. Asch

Research funding: Forty Seven, MEI Pharma, Astellas Pharma, Car-

tesian Therapeutics, MacroGenics, Juno Therapeutics

Other remuneration: provisional Patent submitted: Immediate Family

Member

J. D. Soumerai

Consultant or advisory role: Abbvie, BeiGene, Bristol‐Myers Squibb,

TG Therapeutics

Research funding: Genentech/Roche, BeiGene, TG THerapeutics,

BostonGene, Glaxo SmithKline, Adaptive Biotechnologies

J. Llorin‐Sangalang

Employment or leadership position: Medical Director‐MEI

Pharma

I. Gorbatchevsky

Employment or leadership position: VP‐Clinical Development MEI

Pharma

J. Li

Employment or leadership position: Senior Director: Biometrics‐MEI

Pharma

A. D. Zelenetz

Consultant or advisory role: Gilead, Amgen, Genetech/Roche, Cel-

gene, DAVOncology, MorphoSys, BeiGene, MEI Pharma, Vaniam

Group, Verastem, Pharmacyclics, Karyopharm, debiopharm, Seattle

Genetics, Quant Health, Kite, curis, Coherus Biosciences, Juno, BMS,

Curio Science

Honoraria: NCCN, Clinical Care Options, PER, Plexus, Oncology In-

formation Group

Research funding: Genentech/Roche, gilead, MEI Pahrma, Beigene

114 |OUTCOMES IN LATER‐LINES OF THERAPY FOR

RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA: RESULTS

FROM THE INTERNATIONAL SCHOLAR‐5 STUDY

P. Ghione

, H. Ghesquieres

, S. Bobillo

, A. R. Patel

, S. Kanters

, K.

Deighton

, H. Dong

, Y. Yang

, L. Ma

, E. H. Limbrick‐Oldﬁeld

, J.

Thornton Snider

, S. W. Wade

, M. T. Riberio

, A. Sudhindra

, J.

Radford

, M. L. Palomba

, J. Gribben

Roswell Park Comprehensive Cancer Center and Memorial Sloan

Kettering Cancer Center, Buffalo and New York, New York, USA,

Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France,

Vall

D’Hebron Insitute of Oncology, Department of Haematology and

Oncology, Barcelona, Spain,

Kite, A Gilead Company, Santa Monica, USA,

RainCity Analytics, Vancouver, Canada,

Delta Hat, Nottingham, UK,

Wade Outcomes Research and Consulting, Salt Lake City, Utah, USA,

Portuguese Oncology Institute of Porto, Porto, Portugal,

The Christie

NHS Foundation Trust and University of Manchester, Manchester, UK,

Memorial Sloan Kettering Cancer Center, New York, New York, USA,

Cancer Research UK Barts Centre, London, UK

Background: Follicular lymphoma (FL) patients may receive many

lines of treatment (LoTs) to maintain disease control. Current clinical

outcomes in later LoTs (≥3

) are not well deﬁned. The international

SCHOLAR‐5 study sought to describe treatment patterns and clinical

outcomes of real‐world later LoTs for FL.

Methods: This multicentre retrospective cohort was conducted at

major lymphoma centres in the US and Europe. Adult (≥18) patients

diagnosed with grade 1‐3a FL, initiating (after 7/2014) a new treat-

ment post ≥2 previous LoTs were enrolled. Radiotherapy or anti‐

CD20 therapy alone were not considered prior LoTs. Patients that

transformed before index date were excluded. Objective response

rate (ORR), complete response (CR), progression free survival (PFS)

and overall survival (OS) were analysed by LoT. Time‐to‐event out-

comes were determined by Kaplan‐Meier. A subgroup analysis was

conducted among 3

LOT patients who progressed within 24 months

of initiating ﬁrst‐line chemo‐immunotherapy (POD24).

TABLE 1: Outcome Results

174

SUPPLEMENT ABSTRACTS

Results: Data from 184 patients were extracted, of whom 123 fulﬁlled

the inclusion criteria. Of the 123, 99 initiated a 3

LoT, 54 initiated a

LoT, and 27 initiated ≥5

LoTs. Proportions with high‐risk attri-

butes included 31% with POD24, 43% with refractory disease and 44%

with stage 3 or higher at the start of their ﬁrst eligible (≥3) LoT. Median

time from initial diagnosis to initiation of 3

LoT was 84 months overall

and 44 months in the POD24 patients. The most commonly used

regimen in 3

LoT (37%) was chemo‐immunotherapy; in ≥4

LoT were

experimental drug‐based (33%) or chemo‐immunotherapy (33%); and

in ≥5

LoT was chemo‐immunotherapy (28%). ORR at 3

LoT was 67%

(CR 42%), decreasing after each subsequent LoT. OS and PFS at 18

months after 3

LoT were 84% and 35% respectively but decreased to

40% and 3% in ≥5th LoTs. In subgroup analysis, the POD24 group had

much lower median and 18‐month PFS at 3

LoT compared with the

non‐POD24 group (Table 1).

Conclusions: Even after excluding cases of transformation, FL patients

respond less and for shorter time to treatment after each LoT. Addi-

tionally, PFS decreases dramatically among POD24 patients. These

ﬁndings demonstrate an unmet need in later‐line FL. Data from addi-

tional subjects are being collected and analysis will be updated for the

meeting.

The research was funded by: Kite, a Gilead Company

Keywords: Indolent non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

H. Ghesquieres

Consultant or advisory role: Gilead Sciences, Celgene, Roche

Honoraria: Gilead, Janssen, Celgene

Educational grants: Roche, Gilead Sciences, Celgene, Takeda

S. Bobillo

Consultant or advisory role: ROCHE

Educational grants: ROCHE

Other remuneration: Speaker's bureau: ROCHE, GILEAD

A. R. Patel

Employment or leadership position: Kite, A Gilead company

Stock ownership: Kite, A Gilead company

S. Kanters

Employment or leadership position: RainCity Analytics

Research funding: RainCity Analytics has received funds from for‐

proﬁt healthcare companies for research

K. Deighton

Employment or leadership position: Delta Hat

H. Dong

Employment or leadership position: Kite, A Gilead company

Stock ownership: Kite, A Gilead company

Y. Yang

Employment or leadership position: Kite, A Gilead Company

L. Ma

Employment or leadership position: Kite, A Gilead Company

E. H. Limbrick‐Oldﬁeld

Employment or leadership position: RainCity Analytics

J. Thornton Snider

Employment or leadership position: Kite, A Gilead Company

Stock ownership: Gilead Sciences

Research funding: Previously employed at PrecisionHEOR, which

receives research funding from life sciences companies.

S. W. Wade

Consultant or advisory role: Kite Pharma, Amgen, Allergan

A. Sudhindra

Employment or leadership position: Atara Biotherapeutics, Kite

Pharma

Stock ownership: Atara Biotherapeutics, Gilead

J. Radford

Consultant or advisory role: Takeda/ADCT/BMS/Novartis/

KitePharma

Stock ownership: ADCT & AZ (spouse)

Honoraria: akeda/ADCT/BMS/Novartis/KitePharma

Other remuneration: Speaker's bureau and expert testimony:

Takeda/ADCT

M. L. Palomba

Consultant or advisory role: Novartis, Kite, PCYC, BeiGene

Stock ownership: Seres, Notch

Research funding: Seres

Other remuneration: Patents, royalties. other IP: Juno, Seres, Wol-

ters Kluwer

J. Gribben

Consultant or advisory role: AZ

Research funding: Janssen, AZ

115 |OUTCOME OF 133 PATIENTS WITH FOLLICULAR

LYMPHOMA (FL) PROGRESSING BEFORE 24 MONTHS (POD24)

AFTER IMMUNOCHEMOTHERAPY: A GELTAMO STUDY

A. Muntañola

, L. Magnano

, S. Mercadal

, M. Huguet

, S. Bobillo

, M.

Bastos‐Oreiro

, A. Jiménez‐Ubieto

, J. Rovira

, A. Rivero

M. Alcoceba

, P. Mozas

, L. Luizaga

, S. Alonso‐Álvarez

, A. Rivas‐

Delgado

, E. Giné

, D. Caballero

, J. M. Sancho

, A. López‐Guillermo

Hospital Universitari Mútua Terrassa, Hematology, Barcelona, Spain,

Hospital Clínic Barcelona, Hematology, Barcelona, Spain,

Hospital

Duran Reynals ‐ICO Hospitalet, Hematology, Barcelona, Spain,

Hospital

Germans Trias i Pujol ‐ICO Badalona, Hematology, Barcelona, Spain,

Hospital Vall d'Hebron, Hematology, Barcelona, Spain,

Hospital

Universitario Gregorio Marañón, Hematology, Madrid, Spain,

Hospital

Universitario 12 de Octubre, Hematology, Madrid, Spain,

Hospital

Universitari Joan XXIII ‐ICO Tarragona, Hematology, Tarragona, Spain,

Hospital Universitario de Salamanca, Molecular Biology, Salamanca,

Spain,

Hospital Universitari Mútua Terrassa, Pathology, Barcelona,

Spain,

Hospital Universitario Central de Asturias, Hematology, Oviedo,

SUPPLEMENT ABSTRACTS

175

Spain,

Complejo Asistencial Universitario de Salamanca /IBSAL,

Hematology, Salamanca, Spain

Introduction: Patients with FL have prolonged survival, but with a

clinical course of successive relapses. Patients progressing before 24

months (POD24) have been identiﬁed as a poor prognosis subset

with 5‐year survival about 50%. Nevertheless, this group is hetero-

geneous with some cases showing notable survival after 1

relapse/

progression. The aim of this study was to characterize POD24 FL

population and to identify main prognostic factors at progression.

Patients and methods: 133 patients (66M/67F; median age at ﬁrst

relapse 58 years) diagnosed with grades 1‐3a FL in 9 GELTAMO

centers, treated with immunochemotherapy (71% R‐CHOP), plus

maintenance with rituximab in 42 (32%), who have progressed before

24 months from starting therapy were the subjects of the present

study. Cases showing histological transformation at progression/

relapse were not included.

Results: Main clinical features at time of progression were the

following: advanced stage, 75%; bone marrow involvement, 26%; four

or more nodal areas, 52%; high serum LDH and beta2‐microglobulin,

33% and 31%, respectively. Distribution by FLIPI was: low‐risk 26%,

intermediate‐risk 29%, high‐risk 45%. Salvage treatment consisted in

immunochemotherapy (ESHAP regimen in most cases) in 39% of cases,

purine analogs in 38% and other in 23%. Response was assessable in

108 cases, with a proportion of CR and PR of 51% and 30%, respec-

tively. 21 patients (16%) in response received intensiﬁcation with

ASCT at this point. 10‐year progression‐free survival from salvage was

26% (95%CI 18‐34%). After a median follow‐up of 11.5 years, 75 pa-

tients have died, with a 10‐year survival from POD24 (SFPOD24) of

43% (95%CI: 34‐52%) (ﬁgure A). Variables at the time of relapse pre-

dicting poor survival were the following: age >60 years (p <0.001),

high LDH (p <0.001), Hb <12 g/dL (p <0.001), advanced Ann‐Arbor

stage (p <0.001), higher‐risk FLIPI (p <0.001) (ﬁgure B). As ex-

pected, patients reaching CR after salvage showed better SFPOD24

than the other groups (ﬁgure C). However, patients in response in

whom ASCT was performed did not have better SFPOD24 than those

responding cases managed without transplant. In the multivariate

analysis only FLIPI score at relapse (low/intermediate vs. high, p =

0.040; HR 0.51) and response to salvage therapy (CR vs. PR/NR, p <

0.001; HR 0.15) maintained prognostic signiﬁcance for SFPOD24.

Conclusion: Although overall the outcome of POD24 FL patients is

poor, a considerable group of them, i.e., low‐intermediate FLIPI

and those reaching CR after salvage, still have a favorable

prognosis.

Keywords: Diagnostic and Prognostic Biomarkers, Indolent non‐

Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

116 |BENDAMUSTINE‐RITUXIMAB COMPARED TO

RITUXIMAB‐CHOP/CVP FOR TREATMENT OF PATIENTS WITH

INDOLENT LYMPHOMA IN ONTARIO: A POPULATION‐BASED

STUDY

A. Suleman

, S. Aktar

, N. Liu

, K. Chan

, M. Cheung

, A. Prica

University of Toronto, Department of Medicine, Toronto, Canada,

Institute for Clinical Evaluative Sciences, (ICES), Toronto, Canada,

Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto,

Canada,

Princess Margaret Cancer Centre, Cancer Clinical Research Unit,

Toronto, Canada

Introduction: For patients with symptomatic advanced stage indolent

lymphoma, rituximab (R) was traditionally used alongside cyclo-

phosphamide, vincristine, prednisone (CVP), or cyclophosphamide,

doxorubicin, vincristine, and prednisone (CHOP). Bendamustine plus

rituximab (BR) has been found to increase progression‐free survival

compared to R‐CHOP/CVP, although controversy exists around its

toxicity proﬁle. Since 2013, bendamustine has been approved for

universal public reimbursement for this indication in Ontario, Can-

ada, and become the preferred regimen. We examined survival and

toxicity of patients with indolent lymphoma treated with BR

compared with RCVP/CHOP in Ontario.

Methods: We conducted a retrospective cohort population‐based

study using administrative healthcare databases from Ontario, Can-

ada. Patients with a diagnosis of indolent lymphoma, excluding

mantle cell lymphoma, who were treated with R‐CVP/CHOP from

2005 to 2012 or with BR from 2013‐2018 were included. The two

treatment groups were propensity score matched based on lym-

phoma subtype, age, sex, prior cancer diagnosis, time since diagnosis

and rural/urban residence. The primary outcome of the study is

overall survival (OS) from time of ﬁrst treatment to date of death or

end of study period. Secondary outcomes include toxicities, such as

infections and secondary malignancies, associated resource use, and

outcomes of patients treated with rituximab maintenance therapy.

176

SUPPLEMENT ABSTRACTS

Results: A propensity‐matched cohort of 2029 patients treated with

BR and 2029 patients treated with R‐CVP/CHOP were included. The

median age of patients was 64 years and 48% were female in the

cohort. A majority of patients had a diagnosis of follicular lymphoma

(59.3% of patients treated with BR, 59.7% of patients treated with

R‐CVP/CHOP, p =0.88). Median follow‐up time was 41 and 87

months for patients treated with BR and R‐CVP/CHOP, respectively.

In this well‐matched cohort, BR was associated with a signiﬁcant

improvement in survival compared to R‐CVP/CHOP (HR 0.76, 95%

CI 0.67‐0.88, p <0.01). Five‐year OS was 80% and 75% for patients

treated with BR and R‐CVP/CHOP, respectively (Figure 1). A total of

974 patients died during the follow‐up period (331 treated with BR,

643 treated with R‐CVP/CHOP), of which 875 had causes of death

available. A majority of patients in both groups died from lymphoma

(63.2% treated with BR, 66.4% treated with R‐CVP/CHOP). Death

from secondary malignancies was less common (11.8% treated with

BR, 12.8% treated with R‐CVP/CHOP). Few patients died from

infection (6.2% treated with BR, 3.2% treated with R‐CVP/CHOP).

Conclusions: Our study demonstrates improved OS with BR

compared to R‐CVP/CHOP for patients with previously untreated

indolent lymphoma. Cause of death in both cohorts was most

frequently attributable to lymphoma. This supports BR as the stan-

dard of care for treatment of symptomatic indolent lymphoma.

The research was funded by: This project was in part supported by

the American Society of Hematology HONORS (Hematology Op-

portunities for the Next Generation of Research Scientists) Award

granted to Adam Suleman.

Keywords: Indolent non‐Hodgkin lymphoma, Combination Therapies

No conﬂicts of interest pertinent to the abstract.

117 |MAINTENANCE THERAPY AFTER R‐BENDAMUSTINE VS

R‐CHOP IN FIRST‐LINE TREATMENT OF LOW‐GRADE

FOLLICULAR LYMPHOMA: A MULTICENTRE, RETROSPECTIVE

GELTAMO STUDY

M. Bastos‐Oreiro

, A. Gutierrez

, R. Martín

, A. Cabero

, B. Navarro

A. Jimenez‐Unieto

, C. Alonso

, S. Gonzalez de Villambrosia

, R.

Córdoba

, J. Perez de Oteyza

, María Infante

, R. Del Campo

, A.

De la Fuente

, R. Oña

, D. García Belmonte

, A. Salar

, J. M.

Sancho

Hospital Universitario Gregorio Marañón, Hematology, Madrid, Spain,

Hospital Universitario Son Espases, Hematology, Palma de Mallorca,

Spain,

Hospital Clínico Universitario de Salamanca, Hematology,

Salamanca, Spain,

Hospital Universitario Puerta de hierro, Hematology,

FIGURE 1 Kaplan‐Meier plot of overall survival of the treatment groups from time of treatment initiation

TABLE 1: General Characteristics of the patients and lymphoma at

diagnosis

SUPPLEMENT ABSTRACTS

177

Majadahonda, Spain,

Hospital Universitario 12 de Octubre, Hematology,

Madrid, Spain,

Hospital Arnau de Villanova, Hematology, Valencia, Spain,

Hospital Universitario de Valdecillas, Hematology, Santander, Spain,

Hospital Universitario Fundación Jiménez Díaz, Hematology, Madrid,

Spain,

Hospital Universitario Madrid Sanchinarro, Hematology, Madrid,

Spain,

Hospital Infanta Leonor, Hematology, Madrid, Spain,

Hospital

Universitario Son LLatzer, Hematology, Palma de Mallorca, Spain,

Hospital MD Anderson Madrid, Hematology, Madrid, Spain,

Hospital

de la Zarzuela, Hematology, Madrid, Spain,

Hospital Universitario del

mar, Hematology, Barcelona, Spain,

Hospital Germans Trias i Pujol,

Hematology, Barcelona, Spain

Introduction: After Rituximab (R) plus cyclophosphamide, doxorubicin,

and prednisone (R‐CHOP) induction therapy (IT), the use of R as

maintenance has improved the outcome of patients with follicular

lymphoma (FL). R plus Bendamustine (R‐B) has demonstrated excellent

efﬁcacy in this setting, but the role of maintenance (MT) is not clear.

Therefore, we compared both R‐based regimens with R maintenance

for untreated advanced‐stage follicular FL and compared their

outcomes.

Methods: We retrospectively assessed patients with FL from 16

different GELTAMO centres, treated with either R‐B or RCHOP as

ﬁrst line therapy followed by maintenance with R. The outcome and

toxicity were evaluated.

Results: A total of 309 patients with FL were included, 93 in the group

that received R‐B and 216 in the group that received R‐CHOP. Pa-

tient's characteristics are resumed in Table 1. R‐B group was older and

Grade 3A signiﬁcantly received more R‐CHOP. All patients completed

induction therapy. G‐CSF prophylaxis and cytopenias during IT were

more frequent with R‐CHOP (Table 1), infections rates were similar (R‐

B 22 [24,2%] vs R‐CHOP 51 [25,4%], p =0.8). Seventy patients (73%) in

the R‐B group and 193 (88%) in the R‐CHOP group completed MT.

Discontinuation was more frequent in R‐B group, the most common

reasons were cytopenias and infections (Table 2s). Infection related

TABLE 2: Treatment Characteristics and complications

178

SUPPLEMENT ABSTRACTS

deaths were more frequent in the R‐B group (40% vs 7%, p =0.051).

We didn’t ﬁnd differences in 2

neoplasms.

Complete response at the end of IT and progression rates were

similar in both groups (87% in R‐B, 90% in R‐CHOP, and 7.8% in R‐B

6.3% in R‐CHOP respectively). Relapses were more frequent in R‐

CHOP (8% in R‐B, 21.8% in R‐CHOP, p =0.019). POD 24 was

similar for both groups (9 [10%] for R‐B and 21 [10%] for R‐CHOP).

After a median follow‐up of 6.2 years (5,1 for R‐B and 6,5 for R‐

CHOP), 5‐year rate of progression‐free survival was 84% for R‐B

vs.75% for R‐CHOP, (95% conﬁdence interval [CI], 0,79 to 2,6; p =

0.2). (Figure 1) and overall survival, 87% for R‐B vs. 91% for R‐CHOP,

(95% [CI], 0.21 to 1.52; p =0.3).

Conclusion: In this series, R‐CHOP and R‐bendamustine showed

similar efﬁcacy in untreatead advanced‐stage FL. However, mainte-

nance after R‐B was associated with more toxicity, especially neu-

tropenia and infections.

Keywords: Indolent non‐Hodgkin lymphoma, Immunotherapy

No conﬂicts of interest pertinent to the abstract.

118 |OBINUTUZUMAB CAN BE ADMINISTERED AS A 90‐

MINUTE SHORT‐DURATION INFUSION (SDI) IN PATIENTS WITH

PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA: GAZELLE

END OF INDUCTION ANALYSIS

K. Hübel

, T. A. Buchholz

, K. Izutsu

, T. Ishikawa

, L. M. Fogliatto

, E.

Vorozheikina

, D. Klingbiel

, S. Pokala

, M. Tomiczek

, J. Parreira

M. A. Canales

Uniklinik Köln, Department of Internal Medicine 1, Köln, Germany,

Scripps MD Anderson Cancer Center, San Diego, USA,

National Cancer

Center Hospital, Department of Hematology, Tokyo, Japan,

Kobe City

Medical Center, General Hospital, Department of Hematology, Hyogo,

Japan,

Hospital de Clínicas de Porto Alegre, Department of Hematology,

Porto Alegre, Brazil,

IQVIA, Medical and Scientiﬁc Services, Moscow,

Russian Federation,

F. Hoffmann‐La Roche Ltd, Product Development

Biometrics, Basel, Switzerland,

F. Hoffmann‐La Roche Ltd, Product

Development Safety, Basel, Switzerland,

F. Hoffmann‐La Roche Ltd,

Product Development Clinical Operations, Basel, Switzerland,

Hoffmann‐La Roche Ltd, Product Development Medical Affairs, Basel,

Switzerland,

Hospital Universitario La Paz, Department of Hematology,

Madrid, Spain

Introduction: Obinutuzumab (G)‐chemotherapy has demonstrated

improved PFS compared with rituximab (R)‐chemotherapy in previ-

ously untreated advanced follicular lymphoma (FL). G is currently

administered by IV infusion over 3–4 hrs. G SDI from Cycle (C) 2

onwards could be advantageous for pts and infusion facilities. We

report the end of induction (EOI) analysis of the Phase IV GAZELLE

study (NCT03817853), which evaluated a 90‐minute (min) G SDI in

pts with FL.

Methods: Pts with previously untreated FL who met GELF criteria

received G (1000mg) IV on Day (D) 1, 8 and 15 of C1, and on D1

thereafter, plus chemotherapy (bendamustine, CHOP or CVP) for 6–8

cycles. In C1, pts received G at the standard infusion rate. Pts without

a Grade (Gr) ≥3 infusion‐related reaction (IRR) in C1 received G as a

FIGURE 1 Progression‐free survival and Overall survival comparing R‐B and R‐CHOP

TABLE: SDI duration during induction

SDI duration D1 D8 15 C2 C3 C4 C5 C6 C7 C8

Median duration, mins

(min‐max)

269.5 (115‐

1630)

210.0 (82‐

357)

205.0 (80‐

335)

98.0 (53‐

193)

95.0 (66‐

750)

96.0 (88‐

195)

95.5 (75‐

245)

96.0 (89‐

183)

95.0 (63‐

160)

95.0 (88‐

105)

Duration ≤110 mins,

n (%)

0/ 4/ 2/ 106/ 105/ 102/ 101/ 98/ 51/ 52/

113 112 (3.6) 111 (1.8) 110 (96.4) 108 (97.2) 108 (94.4) 107 (94.4) 105 (93.3) 55 (92.7) 52 (100)

SUPPLEMENT ABSTRACTS

179

90‐min SDI from C2 onwards. Pts with a Gr 3 IRR in C1 received G at

the standard infusion rate in C2, and received G SDI from C3 onwards

if no Gr ≥3 IRR occurred. Pts with a second Gr 3 IRR discontinued G.

At EOI, responding pts received maintenance G (1000mg) as SDI for 2

yrs or until PD. The primary endpoint was incidence of Gr ≥3 IRR

during C2. IRR was deﬁned as any event occurring during or within 24

hrs of infusion and judged related to treatment.

Results: As of December 3, 2020, 113 pts had completed EOI

treatment. Median age was 62.0 yrs, 50.4% were male, 61.9% had

stage IV FL and 45.1% were classiﬁed as high‐risk FLIPI. Of the

110 pts who received G SDI in C2, none experienced a Gr ≥3 IRR.

One patient experienced a Gr 3 IRR with SDI in C5 (hypertension).

All other IRRs with SDI were Gr 1/2. Median SDI duration in C2–8

was 95–98 mins, and SDI duration was ≤110 mins in >90% of pts

(Table). From C1 onwards, AEs were reported in 99.1% (112/113)

of pts. Gr ≥3 AEs were observed in 72.6%. Common Gr ≥3 AEs

(>5%) were neutropenia (50.4%), leukopenia (11.5%), lymphopenia

(10.6%), thrombocytopenia (7.1%), IRR (6.2%) and febrile neu-

tropenia (5.3%). Gr 5 (fatal) AEs were reported in 2 pts (cardiac

arrest and aspiration pneumonia; both considered unrelated to

treatment). CT‐imaging at EOI demonstrated that: 76/113 (67.3%)

pts had a CR; 22 (19.5%) had a PR; and six (5.3%) had PD; 9 pts

had no response assessment.

Conclusions: In GAZELLE, G SDI from C2 onwards appeared to be

safe. No Gr ≥3 IRRs were observed in C2 and only one Gr 3 IRR was

reported in subsequent cycles. No new safety signals were reported

and response data were in line with previous studies. SDI time was

≤110 mins in >90% of pts. G SDI is likely to improve convenience for

pts and efﬁciency for infusion facilities.

The research was funded by: GAZELLE is sponsored by F. Hoffmann‐

La Roche Ltd (NCT03817853).

Keywords: Indolent non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

K. Hübel

Consultant or advisory role: F. Hoffmann‐La Roche Ltd, Gilead, Hexal,

EUSA

Research funding: F. Hoffmann‐La Roche Ltd, Celgene, Hexal,

Janssen

Educational grants: F. Hoffmann‐La Roche Ltd, Celgene, Hexal

Other remuneration: Speakers' bureau ‐F. Hoffmann‐La Roche Ltd,

Celgene, EUSA

T. A. Buchholz

Employment or leadership position: Scripps Health Care System,

Nucleix, Empyrean Medical Systems

Consultant or advisory role: Genentech, Inc., F. Hoffmann‐La Roche Ltd

Stock ownership: Nucleix, Empyrean Medical Systems

Honoraria: Genentech, Inc., F. Hoffmann‐La Roche Ltd, Abivax,

Precisa

Educational grants: Genentech, Inc.

Other remuneration: MD Anderson Cancer Center

K. Izutsu

Honoraria: Chugai Pharmaceutical

Research funding: Chugai Pharmaceutical

E. Vorozheikina

Employment or leadership position: IQVIA, Associate medical director

D. Klingbiel

Employment or leadership position: F. Hoffmann‐La Roche Ltd

Stock ownership: F. Hoffmann‐La Roche Ltd

M. Tomiczek

Employment or leadership position: F. Hoffmann‐La Roche Ltd

J. Parreira

Employment or leadership position: F. Hoffmann‐La Roche Ltd

Stock ownership: F. Hoffmann‐La Roche Ltd

Honoraria: F. Hoffmann‐La Roche Ltd

M. A. Canales

Consultant or advisory role: Astellas, Eusa Pharma, Celgene, Gilead,

Janssen, Karyopharm, Novartis, F. Hoffmann‐La Roche Ltd, Takeda

Honoraria: Amgen, Gilead, Janssen, F. Hoffmann‐La Roche Ltd,

Takeda

Educational grants: Gilead, Janssen, Novartis, F. Hoffmann‐La Roche

Ltd

119 |UPDATED RESULTS OF THE FIL “MIRO” STUDY, A

MULTICENTER PHASE II TRIAL COMBINING LOCAL

RADIOTHERAPY AND MRD‐DRIVEN IMMUNOTHERAPY IN

EARLY‐STAGE FOLLICULAR LYMPHOMA

A. Pulsoni

, M. E. Tosti

, S. Ferrero

, S. Luminari

, A. Dondi

, A. M.

Liberati

, N. Cenfra

, D. Renzi

, M. Zanni

, C. Boccomini

, A. J.

Ferreri

, S. Rattotti

, V. R. Zilioli

, P. Bernuzzi

, S. Bolis

, G.

Musuraca

, L. Nassi

, T. Perrone

, C. Stelitano

, A. Anastasia

, P.

Corradini

, G. Partesotti

, F. Re

, E. Cencini

, C. Mannarella

, D.

Mannina

, A. L. Molinari

, M. Tani

, G. Annechini

, G. M. Assanto

L. Grapulin

, A. Guarini

, M. Cavalli

, L. A. De Novi

, E. Ciabatti

, B.

Mantoan

, I. Della Starza

, L. Arcaini

, U. Ricardi

, V. Gattei

, S.

Galimberti

, M. Ladetto

, R. Foà

, I. Del Giudice

Hematology, Sapienza University, Department of Translational and

Precision Medicine, Roma, Italy,

Istituto Superiore di Sanità, National

Center for Global Health, Roma, Italy,

Hematology Division, University of

Torino/AOU "Città della Salute e della Scienza di Torino", Department of

Molecular Biotechnologies and Health Sciences, Torino, Italy,

Hematology

Unit, Arcispedale S. Maria Nuova, Azienda Unità Sanitaria Locale ‐IRCCS,

University of Modena and Reggio Emilia, Reggio Emilia, Italy,

Fondazione

Italiana Linfomi Onlus, (FIL), Modena, Italy,

A.O. Santa Maria Terni,

University of Perugia, Perugia, Italy,

Hematology Unit, S. Maria Goretti

Hospital , AUSL Latina, Latina, Italy,

Hematology and Stem Cells

Transplantation Unit, IRCCS Istituto Nazionale dei Tumori Regina Elena,

Roma, Italy,

Division of Hematology, SS. Antonio e Biagio Hospital,

Alessandria, Italy,

Hematology Department, Città della Salute e della

180

SUPPLEMENT ABSTRACTS

Scienza, Torino, Italy,

Lymphoma Unit, IRCCS San Raffaele Scientiﬁc

Institute, Department of Onco‐Haematology, Milano, Italy,

Division of

Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy,

Di-

vision of Hematology, ASST Grande Ospedale Metropolitano Niguarda,

Milano, Italy,

Hematology Unit, Guglielmo da Saliceto Hospital, Depart-

ment of Onco‐Hematology, Piacenza, Italy,

Hematology Department,

ASST San Gerardo University Hospital, Monza, Italy,

Hematology Unit,

IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”,

Meldola (FC), Italy,

Division of Hematology, University of Eastern Pied-

mont, Department of Translational Medicine, Novara, Italy,

Unit of He-

matology with Transplantation, University of Bari, Dept. of Emergency and

Organ Transplantation, Bari, Italy,

Department of Haematology, Azienda

Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy,

Hematol-

ogy, ASST Spedali Civili di Brescia, Brescia, Italy,

Division of Hematology,

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy,

Onco‐Hematology Department, Nuovo ospedale civile of Sassuolo, Sas-

suolo, Italy,

Hematology Clinic, A.O.U. di Parma, Parma, Italy,

Unit of

Hematology, Azienda Ospedaliera Universitaria Senese & University of

Siena, Siena, Italy,

Hematology Unit, "Madonna delle Grazie" Hospital,

Matera, Italy,

Department of Hematology, Azienda Ospedaliera Papardo,

Messina, Italy,

Hematology, Ospedale degli Infermi, Rimini, Italy,

He-

matology Unit, Santa Maria delle Croci Hospital, Ravenna, Italy,

Depart-

ment of Radiotherapy, Policlinico Umberto I, Sapienza University, Roma,

Italy,

Hematology, Sapienza University, Department of Molecular Medi-

cine, Roma, Italy,

Section of Hematology, University of Pisa, Department

of Clinical and Experimental Medicine, Pisa, Italy,

Hematology Division,

University of Torino, Department of Molecular Biotechnologies and Health

Sciences, Torino, Italy,

Division of Hematology, Fondazione IRCCS Poli-

clinico San Matteo, University of Pavia, Department of Molecular Medicine,

Pavia, Italy,

Radiation Oncology, University of Turin, Department of

Oncology, Torino, Italy,

Clinical and Experimental Onco‐Hematology Unit,

CRO Aviano National Cancer Institute, Aviano, Italy,

Section of Hema-

tology, University of Pisa, Department of Clinical and Experimental Medi-

cine, Pisa, Italy,

Hematology, Az Ospedaliera Santi Antonio e Biagio e

Cesare Arrigo, Università del Piemonte Orientale, Alessandria, Italy

Background: Early‐stage follicular lymphoma (FL) is usually managed

with involved ﬁeld radiotherapy (IFRT), allowing a complete and long

lasting eradication of the disease only in 40‐50% of patients (pts). The

aim of this multicenter phase II prospective study was to evaluate the

role of MRD in identifying pts unlikely to be cured by IFRT, for whom

an immunotherapy consolidation could improve outcome.

Methods: 110 pts with stage I/II FL were enrolled and treated with

24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples

were centralized to the FIL (Fondazione Italiani Linfomi) MRD

Network of EuroMRD‐certiﬁed laboratories. In BCL2/IGH+pts at

baseline by both nested PCR (NEST) and RQ‐PCR (RQ) in BM a/o PB,

MRD was analyzed after IFRT and every 6 months over a 3‐year

period. Pts with MRD+by both NEST and RQ in BM a/o PB after

IFRT or who became MRD+during the follow‐up were treated with 8

weekly doses of the anti‐CD20 MoAb ofatumumab (OFA). The pri-

mary objective of the study was to deﬁne the efﬁcacy of immuno-

therapy in obtaining a negative MRD.

Results: Of the 106 evaluable pts, 50 were males. Median age was 55

y (29‐83). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68%

of pts had inguinal site involvement. At baseline, 30% of pts had a

BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/

o PB; the concordance between compartments was 90%. All but one

pt achieved a clinical response after IFRT; one additional pt died soon

after IFRT of unrelated causes. MRD evaluation after IFRT revealed

the persistence of BCL2/IGH+cells in PB a/o BM in 60% of pts. MRD

+pts, either after IFRT (n =18) or in case of conversion to MRD+

during the follow‐up (n =6), received OFA, obtaining a conversion to

MRD‐in 22/24 pts (91.7% ‐CI 73.0‐99.0), signiﬁcantly superior to

the expected 50% (Fig). After a median F‐U of 38 m, 17 pts who

achieved a MRD‐with OFA are still negative; 5 converted to MRD+

(2 received OFA retreatment, achieving a second MRD‐; 2 pts were

not re‐treated due to Sars‐Cov2 pandemic; 1 relapsed). A clinical

relapse or progression was observed in 23 pts: 18 (24.6%) among the

73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+at

baseline (p =0.3), with no signiﬁcant difference in PFS (p =0.25).

Two early relapses were observed among the 12 pts who became

MRD‐after IFRT and 3 among the 24 treated at least once with OFA

(1 MRD+, 1 MRD‐, 1 converted from MRD‐to MRD+). Only 1 Pt

relapsed while MRD‐after OFA.

Conclusions: MRD data indicate that RT alone is often insufﬁcient to

eradicate the disease, inducing a MRD‐only in 40% of pts, notably

long‐lasting only in half of them. The primary objective of this study ‐

MRD conversion after immunotherapy ‐was largely achieved. The

strategy of an immunotherapy consolidation after IFRT in MRD+pts

allowed increasing molecular responses. However, this strategy is

applicable only to 30% of enrolled pts. A clinical advantage of the

MRD driven treatment strategy is suggested although not signiﬁcant.

Keywords: Molecular Targeted Therapies, Immunotherapy

Conﬂicts of interests pertinent to the abstract

A. Pulsoni

Consultant or advisory role: Roche, Merk, Pfyzer, Sandoz;Gylead,

Bristol Meyer Squibb

SUPPLEMENT ABSTRACTS

181

A. J. Ferreri

Consultant or advisory role: Adienne, Gilead, Novartis, Juno,

PletixaPharm

Research funding: BMS, Beigene, Pharmacyclics, Hutchison Medi-

pharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, and

Pﬁzer

V. R. Zilioli

Consultant or advisory role: Roche, Takeda, MSD

Honoraria: Gentili, Gilead

Educational grants: Janssen

120 |CLINICAL OUTCOMES AND THE ROLE OF OBSERVATION

IN EARLY‐STAGE FOLLICULAR LYMPHOMA

F. Sha

, M. Okwali

, A. Alperovich

, P. C. Caron

, L. Falchi

, A.

Hamilton

, P. A. Hamlin

, S. M. Horwitz

, E. Joffe

, A. Kumar

, M. J.

Matasar

, A. J. Moskowitz

, A. Noy

, C. Owens

, L. M. Palomba

, I.

Rodriguez‐Rivera

, D. Straus

, G. von Keudell

, A. D. Zelenetz

, J.

Yahalom

, A. Dogan

, H. Schoder

, V. E. Seshan

, G. Salles

, A.

Younes

, C. L. Batlevi

Memorial Sloan Kettering Cancer Center, Medicine, New York, USA,

Memorial Sloan Kettering Cancer Center, Radiation Oncology, New York,

New York, USA,

Memorial Sloan Kettering Cancer Center, Pathology,

New York, New York, USA,

Memorial Sloan Kettering Cancer Center,

Radiology, New York, New York, USA,

Memorial Sloan Kettering Cancer

Center, Epidemiology and Biostatistics, New York, USA,

Memorial Sloan

Kettering Cancer Center, Medicine; Currently employed at AstraZeneca,

New York, USA

Introduction: Management of early‐stage follicular lymphoma (FL) is

widely variable. We utilized our Follicular Lymphoma Outcomes

Database (FLOD) to assess outcomes and understand the role of

initial observation in patients (pts) with early‐stage FL.

Methods: We retrospectively identiﬁed 295 pts with grade 1‐3A,

stage I‐II FL diagnosed between 1998 and 2009 at Memorial Sloan

Kettering Cancer Center while excluding pts with fully resected

disease, incomplete imaging at diagnosis, and pts not prescribed rit-

uximab in frontline systemic therapy. Pts were categorized as

immediately treated if localized or systemic treatment was started

within 6 months of diagnosis. Pts were stratiﬁed by age at diagnosis

(years): 20‐40 vs. 40‐60 vs. 60‐75 vs. 75‐95, to analyze the per-

centage of immediate treatment or observation in each group.

Results: In the cohort, 137 (46%) pts were initially observed, and 158

(54%) pts received immediate treatment, consisting of radiation

(n =108), systemic treatment (n =29), or combined modality

treatment (n =21). With a median follow‐up of 8.4 years (range 0.3‐

17.2), the estimated 10‐year overall survival (OS) and disease‐

182

SUPPLEMENT ABSTRACTS

speciﬁc survival (DSS) were 87.2% (95% conﬁdence interval [CI]:

0.83‐0.92) and 95.6% (95%CI: 0.93‐0.98), respectively. Age at diag-

nosis did not inﬂuence selection of pts for observation or immediate

treatment (p value 0.98 and 0.75, respectively for stage I and II pts).

In 172 pts with stage I disease, 112 (65%) were immediately treated,

while 60 (35%) were observed. In 123 pts with stage II FL, 46 (37%)

were immediately treated and 77 (63%) were observed. OS in

observed pts was similar to that of immediately treated stage I or

stage II pts (hazard ratio [HR]: 1.51, p =0.41, Fig. A; HR: 0.74, p =

0.48, Fig. D). In stage I or II pts with complete staging with bone

marrow biopsy and PET, OS between observed and immediately

treated pts remain similar (HR: 4.01, p =0.10, Fig. B, HR: 0.25, p =

0.17, Fig. E). The median time to ﬁrst therapy for pts initially

observed with stage I and II disease were 4.73 years (95% CI: 2.66‐

NR, Fig. C) and 6.90 years (95% CI 4.15‐NR, Fig. F), respectively.

Complete staging did not alter median time to ﬁrst therapy signiﬁ-

cantly. PFS for immediately treated pts at 5, and 10 years were

67.6%, and 44.6% for stage I disease, and 46.8%, and 32.2% for stage

II disease. Biopsy‐proven transformation risk using a competing risk

analysis was 4.2% and 10.8% at 5 and 10 years.

Conclusions: This modern‐era analysis conﬁrms the excellent out-

comes of early‐stage FL. Age at diagnosis did not guide selection of

pts for initial observation. Pts selected for observation had a long

duration of observation and similar survival to pts selected for im-

mediate treatment, suggesting initial observation remains an option

in pts with early‐stage FL. Transformation risk endures in early‐stage

FL supporting continual pts monitoring.

The research was funded by: P30 CA008748

Keywords: Indolent non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

L. Falchi

Consultant or advisory role: Genmab.

Research funding: Roche, Genmab.

P. A. Hamlin

Consultant or advisory role: Portola Pharmaceutics, Celgene, Kar-

yopharm, Juno Therapeutics.

Research funding: Portola, Molecular Templates, Incyte, J&J

Pharmaceuticals.

S. M. Horwitz

Consultant or advisory role: ADCT therapeutics, Aileron,Corvus,

Forty‐Seven, Innate Pharma, Kyowa‐Hakka‐Kirin, Millenium/Takeda,

Mundipharma, Portola, Seattle Genetics.

Research funding: ADCT therapeutics, Aileron, Celgene, Forty‐Seven,

Inﬁnity/Verastem, Kyowa‐Hakka‐Kirin, Millenium/Takeda, Seattle

Genetics, Trillium.

E. Joffe

Consultant or advisory role: AstraZeneca, Epizyme.

A. Kumar

Consultant or advisory role: Celgene.

Research funding: Abbvie, Adaptive Biotechnologies, Celgene, Phar-

macyclics, Seattle Genetics.

M. J. Matasar

Consultant or advisory role: Genentech, Bayer, Merck, Juno, Roche,

Teva, Rocket Medical, Seattle Genetics.

Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle

Genetics, GlaxoSmithKline.

Research funding: Genentech, Roche, GlaxoSmithKline, Bayer, Phar-

macyclics, Janssen, Rocket Medical, Seattle Genetics.

Educational grants: Genentech, Roche, Seattle Genetics, Bayer.

A. J. Moskowitz

Consultant or advisory role: Kyowa Hakko Kirin Pharma, Miragen

Therapeutics, Takeda Pharmaceuticals, ADC therapeutics, Seattle

Genetics, Cell Medica, Bristol‐Myers Squibb, Erytech Pharma.

Research funding: Incyte, Seattle Genetics, BMS, and Merck.

A. Noy

Consultant or advisory role: Janssen, Pharmacyclics, Medscape,

Targeted Oncology.

Research funding: Pharmacyclics, NIH, Raphael Pharma.

L. M. Palomba

Honoraria: Merck, Celgene, Juno and Pharmacyclics.

D. Straus

Consultant or advisory role: Seattle Genetics.

Research funding: Seattle Genetics.

G. von Keudell

Research funding: Pharmacyclics, Merck, Epizyme.

A. D. Zelenetz

Consultant or advisory role: Genentech/Roche, Kite/Gilead, Quant

Health, Astra Zeneca; Karyopharm, Adaptive Biotechnology; Mor-

phoSys, JUNO/Celege/BMS, BeiGene, Verastem.

Research funding: MEI Pharma, Genentech/Roche, BeiGene, Adap-

tive BIotechnology.

A. Dogan

Honoraria: Corvus Pharmaceuticals, Physicians’ Education Resource,

Seattle Genetics, Takeda, Roche, EUSAPharma, PeerView.

Research funding: Roche and Takeda.

G. Salles

Consultant or advisory role: Abbvie, Beigene, BMS/Celgene, Debio-

pharm, Genentech/Roche, Genmab, Incyte, Ipsen, Kite/Gilead, Mil-

teniy, Morphosys, Novartis, Velosbio.

A. Younes

Employment or leadership position: Employed by AstraZeneca.

Consultant or advisory role: Biopath, Xynomics, Epizyme, Roche.

Honoraria: Janssen, AbbVie, Merck, Curis, Epizyme, Roche, Takeda.

Research funding: Janssen, Curis, Merck, BMS, Syndax, and Roche.

C. L. Batlevi

Honoraria: Dava Oncology.

Research funding: Janssen, Novartis, Epizyme, Xynomics.

SUPPLEMENT ABSTRACTS

183

121 |EARLY METABOLIC RESPONSE IN FOLLICULAR

LYMPHOMA: A SUBSET ANALYSIS OF THE FOLL12 TRIAL BY THE

FONDAZIONE ITALIANA LINFOMI (FIL)

S. Luminari

, L. Guerra

, R. Durmo

, S. Chauvie

, S. Peano

A. Franceschetto

, F. Fallanca

, V. Tarantino

, A. Pinto

, C. Ghiggi

A. Pulsoni

, M. Merli

, L. Farina

, M. Tani

, B. Botto

G. Musuraca

, B. Falini

, F. Ballerini

, P. M. Stefani

, S. Bolis

G. Pietrantuono

, M. Manni

, L. Marcheselli

, M. Federico

A. Versari

Azienda Unità Sanitaria Locale IRCCS, Arcispedale Santa Maria Nuova

IRCCS, Hematology Unit and University of Modena and Reggio Emilia,

Surgical, Medical and Dental Department of Morphological Sciences

related to Transplant, Oncology and Regenerative Medicine, Reggio Emilia,

Italy,

S. Gerardo Hospital, University of Milano‐Bicocca, Nuclear Medi-

cine and , University of Milano Bicocca, School of Medicine and Surgery,

Monza, Italy,

Azienda USL‐IRCCS di Reggio Emilia, Nuclear Medicine,

Reggio Emilia, Italy,

Santa Croce e Carle Hospital, Department of Medical

Physics, Cuneo, Italy,

ASO S. Croce e Carle, S.C. Medicina Nucleare,

Cuneo, Italy,

Modena Cancer Center, University of Modena and Reggio

Emilia, Department of Oncology and Hematology, Unit of Nuclear Medi-

cine, Modena, Italy,

IRCCS San Raffaele Scientiﬁc Institute, Nuclear

Medicine Unit, Milano, Italy,

University of Modena and Reggio Emilia,

PhD program in Clinical and Experimental Medicine (CEM), Modena, Italy,

National Cancer Institute, Fondazione “G. Pascale” IRCCS, Hematology‐

Oncology and Stem Cell Transplantation Unit, Napoli, Italy,

IRCCS San

Martino Hospital, Hematology and Transplant Center Division, Genoa,

Italy,

Sapienza Università di Roma, Dipartimento di Biotecnologie Cel-

lulari ed Ematologia, Roma, Italy,

University Hospital Ospedale di Cir-

colo e Fondazione Macchi, ASST Settelaghi, Varese, Italy,

Fondazione

IRCCS Istituto Nazionale dei Tumori di Milano , Division of Hematology,

Milano, Italy,

Ospedale Civile S Maria delle Croci, Azienda Unità Sani-

taria Locale (AUSL), Ravenna, Italy,

A.O.U. Città della Salute e della

Scienza di Torino, SC Ematologia, Torino, Italy,

IRCCS Istituto Romag-

nolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Department of He-

matology, Meldola, Italy,

University of Perugia, Institute of Hematology

and CREO (Center for Hemato‐Oncological Research), Ospedale S. Maria

della Misericordia, Perugia, Italy,

IRCCS Ospedale Policlinico San Mar-

tino, University of Genoa, Clinica Ematologica, Genova, Italy,

General

Hospital Ca' Foncello, Hematology, Treviso, Italy,

ASST MONZA, SC di

Ematologia, Monza, Italy,

IRCCS Centro di Riferimento Oncologico della

Basilicata, Hematology and Stem Cell Transplantation Unit, Rionero in

Vulture, Italy,

University of Modena and Reggio Emilia, Surgical, Medical

and Dental Department of Morphological Sciences related to Transplant,

Oncology and Regenerative Medicine, Modena, Italy,

Fondazione Ital-

iana Linfomi Onlus, FIL, Modena, Italy

Background: A small but signiﬁcant proportion of patients with

Follicular Lymphoma (FL) shows an aggressive behavior. Among

available prognostic tools the duration of response and metabolic

response (MR) after completion of immunochemotherapy (ICT)

(fPET) were conﬁrmed with a strong correlation with both PFS and

OS. So far, only few data are available to deﬁne the role of an earlier

assessment of MR during the ICT in FL. In the FOLL12 randomized

trial we evaluated the efﬁcacy of a response adapted post induction

management of patients with FL responding to initial ICT. In a sig-

niﬁcant proportion of patients, MR was also assessed during the

administration of ICT as one of the admitted study procedures. We

here show the details of early assessment of MR and its correlation

with patient outcomes.

Methods: The FOLL12 trial enrolled treatment naïve adult patients

with grade 1‐3a, stage II‐IV and a high tumor burden FL. Complete

FIGURE 1 A)Progression free Survival(PFS) by interim metabolic evaluated with FDS‐PETR at cycle 4 of induction therapy(iPET):B)PFS by

iPET and metabolic response at end of indication PET(fPET)

184

SUPPLEMENT ABSTRACTS

metabolic response (CMR) was centrally assessed at End of Induction

(EOI; fPET) using the 5‐point Deauville scale (DS). In this study we

included only patients for whom MR was also assessed during ICT

between cycle 4 and 5 (iPET). iPET results were deﬁned on the basis of

the local report and were also centrally reviewed applying standard DS.

The primary endpoint was 3‐year Progression Free Survival (PFS).

Results: iPET was performed in 211/807 patients enrolled in the

FOLL12 trial and local report was available in 186 cases. Forty‐eight

percent of patients were older than 60 years, 37% had a high‐risk

FLIPI2, 44% received BR as induction ICT. Based on local report

iPET was considered positive in 38/186 patients (20%). iPET and

fPET were both available for comparison in 174 cases and showed a

concordance rate of 82%: 131 out of 140 iPET‐conﬁrmed their CMR

at fPET (94%). Regarding the 31 iPET+, a fPET‐was achieved in 23

cases (68%). In univariable analysis, the 3‐year PFS was lower for the

iPET+patients compared to the iPET‐(52% vs 87%: HR of 2.73 95%

CI 1.51 – 4.95) (Fig 1A). Considering both iPET and fPET, a positive

iPET was associated with an increased risk of progression also if a

negative fPET was achieved (HR 2.09: 95% CI3.22 – 19.5) (Fig 1B).

iPET was also associated with a different 3‐year OS rate (99% vs 89%

for iPET – vs +; p =0.035). In multivariable analysis the prognostic

role of iPET for PFS was conﬁrmed (HR 2.60 (1.41 – 4.79) and was

independent from FLIPI2 (0‐2 vs 3‐5 HR 1.88 (1.05 – 3.35)), and for

ICT (RB vs R‐CHOP (HR 1.39 (0.77 – 2.51)). The centralized review of

iPET response according to DS is ongoing.

Conclusions: Interim metabolic response is conﬁrmed with a strong

prognostic role for PFS in patients with advanced stage FL treated

with standard ICT. Considering the higher rates of iPET+cases

compared to fPET, iPET may better contribute to anticipate the

identiﬁcation of FL patients at different risk of progression and might

be used to deﬁne a novel generation of response adapted trials in FL.

The research was funded by: ‐Società Italiana di Ematologia (SIE)

‐Associazione Angela Serra per la Ricerca sul Cancro

‐Ministero della Salute, Direzione Generale della ricerca e dell’In-

novazione in sanità (BANDO PROGETTI DI RICERCA GIOVANI

RICERCATORI ‐RICERCA FINALIZZATA 2011‐2012)

Keywords: Diagnostic and Prognostic Biomarkers, PET‐CT, Indolent

non‐Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

122 |THE ROLE OF FDG‐PET/CT AND BONE MARROW BIOPSY

IN DETECTING BONE MARROW INVOLVEMENT IN THE INITIAL

STAGING OF FOLLICULAR LYMPHOMA: AN ANALYSIS OF

ACCURACY AND PROGNOSTIC IMPACT

L. Reguilón Gallego

, T. Chen Liang

, T. Martín Santos

, A. Salar

, M.

Fernández González

, C. Celades

, J. Tomás Navarro

, A.‐B.

Martínez

, R. Andreu

, A. Balaguer Rosello

, A. Martín

, M. Baile

J. López Jiménez

, J. Marquet

, A.‐I. Teruel

, M.‐J. Terol

, C.

Benet

, L. Frutos

, J.‐L. Navarro

, J. Uña

, M. Suarez

, M.

Cortes

, J. Contreras

, C. Ruiz

, P. Tamayo

, J. Mucientes

, P.

Sopena Novales

, J.‐J. Sánchez Blanco

, E. Pérez Ceballos

, A. Jeréz

Cayuela

, F. Ortuño

Hospital Morales Meseguer, IMIB‐Arrixaca, Servicio de Hematología y

Oncología Médica, Murcia, Spain,

Hospital Morales Meseguer, IMIB‐

Arrixaca, Servicio de Hematología y Oncología Médica, Murcia, Spain,

Hospital Universitario de Canarias, Servicio de Hematología, La Laguna,

Tenerife, Spain,

Hospital del Mar, Servicio de Hematología, Barcelona,

Spain,

Hospital Universitario de Canarias, Servicio de Hematología, La

Laguna, Tenerife, Spain,

Josep Carreras Leukaemia Research Institute

(IJC), Servicio de Hematología, Badalona, Spain,

ICO‐H. Germans Trias i

Pujol, Servicio de Hematología, Badalona, Spain,

Hospital Santa Lucía,

Servicio de Hematología, Cartagena, Spain,

Hospital La Fe, Servicio de

Hematología, Valencia, Spain,

Hospital Clínico Universitario de Sala-

manca, Servicio de Hematología, Salamanca, Spain,

Hospital Ramón y

Cajal, Servicio de Hematología, Madrid, Spain,

Hospital Clinico de

Valencia, Servicio de Hematología, Valencia, Spain,

Hospital Arnau de

Villanova, Servicio de Hematología, Valencia, Spain,

Hospital Virgen de la

Arrixaca, Servicio de Medicina Nuclear, Murcia, Spain,

Hospital Uni-

versitario Nuestra Señora de la Candelaria, Servicio de Medicina Nuclear,

Tenerife, Spain,

Hospital del Mar, Servicio de Medicina Nuclear, Barce-

lona, Spain,

Hospital Universitari de Bellvitge‐IDIBELL, Servicio de

Medicina Nuclear, Barcelona, Spain,

Hospital Santa Lucia, Servicio de

Medicina Nuclear, Cartagena, Spain,

Hospital La Fe, Servicio de Medicina

Nuclear, Valencia, Spain,

Hospital Clínico Universitario de Salamanca/

IBSAL, Servicio de Medicina Nuclear, Salamanca, Spain,

Hospital Puerta

de Hierro, Servicio de Medicina Nuclear, Madrid, Spain,

Hospital 9 de

Octubre, Servicio de Medicina Nuclear, Valencia, Spain

Introduction: In the workout of Follicular non‐Hodgkin Lymphoma

(FL), bone marrow assessment by bone marrow biopsy (BMB) is a key

component of Follicular Lymphoma International Prognostic Index‐2

(FLIPI‐2) and progression of disease within 24 months of frontline FL

chemoimmunotherapy initiation (POD24) models. Nevertheless, in

several recent studies, positron emission tomography combined with

computed tomography (PET/CT) identiﬁcation of BMI was shown to be

predictive of progression‐free survival (PFS) and overall survival (OS)

Methods: To evaluate the independent value of BMB and/or PET/CT

to determine bone marrow inﬁltration (BMI) and their prognostic

impact, we have carried out a retrospective multicenter study

including FL patients with both tests at diagnosis. The diagnosis ac-

curacy and the prognosis impact for PFS and OS, and within FLIPI‐2

and POD‐24 models of each technique were analyzed. To avoid

collinearity biases FLIPI‐2 was deconstructed and its ﬁve parameters

were considered independently. In addition, further adjustments

were performed stratifying the whole series by treatment intensity

and histologic grade.

Results: Three hundred two patients were included. Their median age

was 58.3 years, and 50.3% (152 of 302) were female. One hundred

sixty‐one patients (53.3%) had stage IV disease (based on combined

BMB and PET/CT results). The prognostic index scales, FLIPI and

FLIPI‐2, were low risk in 27.5% and 29.5%, respectively. Most pa-

tients had histological grade 1‐2 disease (66.9%). The most common

ﬁrst‐line chemotherapy regimen for advanced‐stage patients was

SUPPLEMENT ABSTRACTS

185

rituximab with cyclophosphamide, doxorubicin, vincristine, and

prednisone in 159 patients (52.6%).

BMI was detected in 170 and 69 patients by BMB and PET/CT

respectively. Sensitivity and accuracy were 46% and 73.2% for PET/CT

and 84.3% and 92.4% for BMB respectively. In univariate analysis both

PET/CT (p=0.043; p=0.01) and BMB (p=0.004; p=0.029) correlated

with PFS and OS, respectively. In a multivariate analysis involving the

whole series, only BMI‐BMB (P=0.043), but not BMI‐PET‐CT corre-

lated with PFS. When considering those patients who received

intensive treatment, only BMI‐BMB (p=0.004; p=0.032) correlated

with PFS and OS, respectively. Among histologic grade 3a patients,

only BMI‐BMB (p=0.01; p=0.009) correlated with PFS and OS,

respectively. However, in other histologic grades (<3), BMI‐BMB (P=

0.009) only correlated with PFS. BMI‐BMB (P=0.03) added inde-

pendent prognostic value to POD‐24 in the multivariate analysis.

When PET/CT was used as positive BMI instead of BMB, it only

added independent prognostic value in the intensive treatment

cohort model (p=0.026) and just for OS.

Conclusions: In our FL series, BMI assessment by BMB was superior

to that of PET/CT in both performance and prognosis and reinforce

the need to carry out BMB for adequately fulﬁll FLIPI‐2.

Keywords: PET‐CT, Indolent non‐Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

123 |CLINICAL UTILITY OF INTERIM CT SCANS IN PATIENTS

RECEIVING CHEMOIMMUNOTHERAPY FOR FIRST LINE

TREATMENT OF FOLLICULAR LYMPHOMA

F. Manji

, S. Bhella

, R. Kridel

, V. Kukreti

, J. Kuruvilla

, A. Prica

, M.

Crump

Princess Margaret Cancer Centre, Department of Medical Oncology and

Hematology, Toronto, Canada

Interim imaging with computed tomography scanning (CT) has been

performed midway through treatment during most clinical trials of

chemoimmunotherapy in patients with follicular lymphoma (FL)

receiving ﬁrst line systemic therapy. Based on this, interim imaging is

commonly performed, but there is little evidence of its utility in clinical

practice.

The objective of this study was to retrospectively review the

outcomes of interim CTs (iCT) in adult patients with biopsy proven FL

(grade 1‐3a, 3b excluded) who met criteria for treatment and

received ﬁrst line therapy with rituximab with cyclophosphamide,

vincristine and prednisone (RCVP) or bendamustine and rituximab

(BR) at Princess Margaret Cancer Centre from January 1 2003‐

December 31 2018. Baseline patient characteristics and treatment

were retrieved from a prospectively populated database, and results

of interim and end of treatment CTs were evaluated from the elec-

tronic medical record. Disease response was assessed using Lugano

response criteria as partial response (PR), complete response (CR),

stable disease (SD) or progressive disease (PD). Descriptive statistics

and Kaplan Meier Survival functions with a log rank test were used

for analysis. The study was approved by the Princess Margaret

Research Ethics Board.

A total of 190 patients were identiﬁed: mean age at diagnosis 58.6

years (IQR 49.2‐67.8), 78% with stage III/IV disease, 26.8% bulky

(>10cm) and 41.1% FLIPI score >2. Patients received either 6‐8 cycles

of RCVP (n =69, 36.3%) or 6 cycles of BR (n =121, 63.7%) with a

median follow up of 75 months (range 6.6‐204.0 months). Most pa-

tients (n =177,93.1%) had interim imaging done between the end of

cycle 2 and prior to cycle 5, most commonly CT scan (n =174,91.5%).

Most iCTs showed a PR (n =147, 77.4 %), with a minority showing a CR

(n =15, 7.9%) and SD (n =8, 4.2 %). Seven patients (3.7%) had PD noted

on iCT. Four patients had a second malignancy identiﬁed on repeat

biopsy of lesions found on iCT (thymoma, poorly differentiated carci-

noma, lung adenocarcinoma and spindle cell tumour), 2 of whom were

symptomatic at the time of imaging. Of the 3 remaining patients, 2 were

symptomatic at the time of iCT and only 1 had asymptomatic PD; all 3

had biopsies demonstrating transformation to diffuse large B cell

lymphoma (DLBCL). The 3 year PFSof all patients was85.29%. Patients

with a PR on iCT had similar 3 year PFS compared to those with CR

(86.25% vs 85.71%, p =.80) as well as overall survival (94.46% vs

92.31%, p =0.58).

Conclusion: iCT is not useful in identifying patients with asymptomatic

early progression of FL during frontline treatment with BR or RCVP.

The majority of patients receiving systemic treatment for FL with BR

or RCVP have at least a PR on iCT, which is not associated with inferior

PFS or OS compared to those with CR. Patients with symptomatic or

asymptomatic PD during treatment warrant biopsy to identify histo-

logic transformation or other malignancies.

EA – previously submitted to ASCO 2021.

The research was funded by: The Princess Margaret Cancer

Foundation

Keywords: Indolent non‐Hodgkin lymphoma

Conﬂicts of interests pertinent to the abstract

S. Bhella

Consultant or advisory role: Celgene

R. Kridel

Research funding: Gilead Sciences, Roche

V. Kukreti

Consultant or advisory role: Kirin Kyoto

J. Kuruvilla

Consultant or advisory role: Abbvie, BMS, Gilead, Karyopharm,

Merck, Roche, Seattle Genetics

Honoraria: Amgen, Antengene, Astra Zeneca, BMS, Gilead, Incyte,

Janssen, Karyopharm, Merck, Novartis, Pﬁzer, Roche, Seattle Ge-

netics, TG Therapeutics

Research funding: Canadian Cancer Society, Leukemia and Lym-

phoma Society Canada, Princess Margaret Cancer Foundation,

Janssen, Roche, Astra Zeneca

186

SUPPLEMENT ABSTRACTS

Other remuneration: Lymphoma Canada (Chair)

A. Prica

Honoraria: Astra‐Zeneca, Gilead

M. Crump

Honoraria: Kite/Gilead, Novartis, Servier

Research funding: Roche, epizyme

124 |WITHDRAWN

125 |EVALUATION OF FOUR PROGNOSTIC INDEXES IN FIRST

LINE FOLLICULAR LYMPHOMA TREATED WITH

IMMUNOCHEMOTHERAPY

C. Fernández‐Rodríguez

, R. Diez‐Feijoo Varela

, B. Sanchez‐

Gonzalez

, L. Bento

, L. Fernández‐Ibarrondo

, J. Gibert

, M.

Lafuente

, J. J. Rodriguez‐Sevilla

, S. Pinzón

, B. Espinet

, A. Ferrer

E. Gimeno

, J. F. García

, R. Ramos

, B. Bellosillo

, A. Gutierrez

, L.

Colomo

, A. Salar

Hospital del Mar, Pathology, Barcelona, Spain,

Hospital del Mar,

Hematology, Barcelona, Spain,

Hospital Son Espases, Hematology, Palma

de Mallorca, Spain,

MD Anderson Cancer Center, Pathology, Madrid,

Spain,

Hospital Son Espases, Pathology, Palma de Mallorca, Spain

Introduction: Several models have been proposed to predict treat-

ment outcome in follicular lymphoma (FL). A new prognostic model

(m7‐FLIPI) incorporated clinical data and mutational status of seven

genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and

CARD11) to predict treatment outcome with front‐line immnuo-

chemotherapy (R‐CHOP and R‐CVP). This model needs further pro-

spective validation in other widely used regimens, such as R‐

bendamustine (R‐B) and also in the real‐world setting.

Methods: Retrospective study from 3 centers that included consec-

utive patients with FL grade 1‐3a treated in ﬁrst line with R‐CVP, R‐

CHOP or R‐B. FFPE tissue from diagnostic lymph node biopsies were

studied by NGS (QIAgen custom DNA panel covering the entire

coding region of 64 genes, including those in the M7‐FLIPI). Gene

libraries were sequenced using Illumina technology.

Results: A total of 191 patients with newly diagnosed FL have been

included in this cohort analysis, with a ﬁnal number of 109 cases with

complete clinical data and successful characterization by NGS. Me-

dian age at diagnosis was 58 years (range 24‐90), 56% were males

and 93.6% had stage III‐IV. Immunochemo was: R‐CVP in 7.3%, R‐

CHOP in 65.1% and R‐B in 27.5%. Overall response rate was

98.2% (CR 83.5%). Maintenance rituximab was administered in

79.8%. With a median follow‐up of 96 months, PFS and OS at 8 years

were 55% and 80%, respectively.

All patients presented mutations (median 8 per patient; range

2‐23). Frequency of m7‐FLIPI genes: EZH2 (23%), ARID1A (17%),

MEF2B (19%), EP300 (19%), FOXO1 (10%), CREBBP (75%),

CARD11 (17%).

FLIPI score was (n =105): low in 18 (17%), intermediate in 45

(43%), high in 42 (40%). m7‐FLIPI score was: low in 81 (77%) and high in

24 (23%). No case with low‐intermediate FLIPI score was upgraded in

m7‐FLIPI. However, 18 out of 42 high‐risk cases in FLIPI were down-

graded to low‐risk m7‐FLIPI. Discrimination according to 4 prognostic

indexes is shown (table). Intriguingly, when R‐B patients were sepa-

rately analyzed, m7‐FLIPI outperformed the other 3 scores for PFS and

OS (log rank/p: 2.818/0.093 and 5.667/0.017, respectively).

Conclusions: In the real‐world setting, all prognostic systems inves-

tigated (FLIPI, FLIPI2, PRIMA and m7‐FLIPI) are useful to identify

patients with different survival probabilities after treatment with

immunochemotherapy, including R‐B. However, FLIPI remains the

prognostic index with higher discrimination.

Acknowledgements: Supported in part by ISCIII, PI15/0459, GLD18/

00117, PI19/0034, 2017SGR205, PT17/0015/0011 and Xarxa de

Banc de Tumors de Catalunya.

The research was funded by: This study was supported in part by

ISCIII, PI15/0459, GLD18/00117, PI19/0034, 2017SGR205, PT17/

0015/0011 and Xarxa de Banc de Tumors de Catalunya.

Keywords: Diagnostic and Prognostic Biomarkers

Conﬂicts of interests pertinent to the abstract

A. Salar

Consultant or advisory role: Celgene, Janssen

Research funding: Gilead

126 |ANALYSIS OF EZH2 MUTATIONS IN SOLID AND LIQUID

BIOPSY AND ITS ROLE AS PREDICTIVE BIOMARKER FOR

CHEMOTHERAPY IN PATIENTS WITH FOLLICULAR LYMPHOMA

L. Sanz‐Villanueva

, F. Díaz Crespo

, R. Martín Rojas

, D. Carbonell

M. Chicano

, J. Suárez‐González

, P. Muñiz

, J. Menárguez

, M. Kwon

J. L. Diez Martín

, I. Buño

, C. Martínez‐Laperche

, M. Bastos Oreiro

Gregorio Marañón Health Research Institute (IiSGM). Gregorio

Marañón General University Hospital, Department of Hematology,

Madrid, Spain,

Gregorio Marañón Gregorio Marañón General

University Hospital, Pathology Department, Madrid, Spain,

Gregorio

Marañón General University Hospital, Department of Hematology,

PFS OS

Log rank

test; p

C‐

index

Log rank

test; p

C‐

index

FLIPI (low‐intermediate

vs high)

11.432;

0.001

0.6435 11.881;

0.001

0.7268

FLIPI2 (low vs

intermediate‐high)

7.038;

0.008

0.5608 6.031;

0.014

0.6023

PRIMA (low vs

intermediate‐high)

7.585;

0.006

0.592 2.057;

0.152

0.6204

m7‐FLIPI (low vs high) 3.146;

0.076

0.6037 3.546;

0.060

0.5737

SUPPLEMENT ABSTRACTS

187

Madrid, Spain,

Gregorio Marañón Health Research Institute (IiSGM).

Gregorio Marañón General University Hospital, Genomics Unit, Madrid,

Spain,

Gregorio Marañón General University Hospital, Department of

Hematology and Pathology, Madrid, Spain,

Gregorio Marañón Health

Research Institute (IiSGM). Gregorio Marañón General University

Hospital, Department of Hematology. Complutense University of

Madrid, Department of Medicine, Madrid, Spain,

Gregorio Marañón

Health Research Institute (IiSGM). Gregorio Marañón General University

Hospital, Department of Hematology and Genomics Unit. Complutense

University of Madrid, Department of Cellular Biology, Madrid, Spain

Introduction: Missense mutations in EZH2 lead to decreased tran-

scriptional function of genes involved in cell cycle regulation and

plasma cell differentiation, contributing to oncogenic transformation.

EZH2 is mutated in near 20% of follicular lymphomas (FL). We aimed

to analyse retrospectively the frequency of mutations in EZH2 at

diagnosis and relapse in tissue and circulating cell free DNA (cfDNA)

in patients with FL and assess the patient's response to therapy,

depending on the EZH2 mutation status.

Methods: We included 179 consecutive patients diagnosed with FL

from 2002 to 2019. Thirty‐seven patients were excluded due to

insufﬁcient DNA quantity or quality. Of the 142 analysed patients, 49

had cfDNA sample at diagnosis. DNA was extracted from tissue bi-

opsies using Maxwell(R) 16 FFPE Plus LEV DNA (Promega). We ob-

tained cfDNA from plasma samples, using QIAamp® Circulating

Nucleic Acid (Qiagen). RT‐qPCR reactions were performed in ctDNA

using PrimeTime Mini LNA probe for EZH2 Y646. Sanger sequencing

were used in tissue DNA for detection of mutations in exon 16

(Y646) and 18 (A682 and A692). Clinical characteristics, therapy and

outcome were collected. Data analysis including descriptive statistics

and Fisher's exact test was performed using IBM SPSS Statistics 26

(IBM, USA).

Results: Of the 142 patients analysed in tissue, 41 (29%) presented

mutations in EZH2 at diagnosis. These mutations were found in 46%

of grade 3B FL and 27% of low‐grade FL (Table 1). Y646N/S/C

mutations in cfDNA were detected in 7/49 (14%) with EZH2

mutated in tissue, 6 of them with stage III‐IV FL. Clinical and bio-

logical characteristics according to EZH2 mutation status in tissue

were compared in patients with lower‐grade FL (Table 1) and high‐

grade 3B. No statistical differences were found in lower‐grade FL.

Instead, patients with grade 3B and mutated EZH2 had statistically

higher FLIPI risk (80% vs 0%; p =0.048) (data not shown). EZH2

mutations in tissue were evaluated at relapse in 13 patients and

were found in 2 samples (3 mutated at diagnosis). Overall survival

(OS) of total cohort and according to therapy received and EZH2

mutation status were compared and there were no statistically

signiﬁcant differences. In terms of progression free survival (PFS),

our results shown that mutated EZH2 patients treated with R‐

bendamustine were signiﬁcantly associated with inferior PFS (p =

0.013) (Figure 1A), unlike R‐CHOP treated patients (p =0.15)

(Figure 1B).

Conclusions: The frequency of EZH2 mutations in our total cohort is

similar to previously reported. Mutations were more frequent in high

grade FL patients. Low‐grade FL patients mutated at diagnosis,

receiving R‐bendamustine were associated with inferior PFS. The

mutational status of these patients at diagnosis could be useful to

guide treatment. Detection of EZH2 mutations in cfDNA is possible in

FL, especially for advanced stages.

TABLE 1Clinical characteristic and ﬁrst‐line theraphy in patents with grade 1,2,3A FL.

188

SUPPLEMENT ABSTRACTS

Keywords: Diagnostic and Prognostic Biomarkers, Liquid biopsy,

Indolent non‐Hodgkin lymphoma

No conﬂicts of interest pertinent to the abstract.

CHRONIC LYMPHOCYTIC LEUKEMIA

127 |CLADRIBINE AS FRONTLINE TREATMENT OF HAIRY CELL

LEUKEMIA: A MULTICENTER EUROPEAN EXPERIENCE OF MORE

THAN 30 YEARS ON 384 PATIENTS

A. Broccoli

, L. Argnani

, M. Cross

, A. Janus

, E. Maitre

, X.

Troussard

, T. Robak

, C. Dearden

, M. Else

, D. Catovsky

, P. L.

Zinzani

IRCCS Azienda Ospedaliero‐Universitaria di Bologna Istituto di Ema-

tologia “Seràgnoli”, and Dipartimento di Medicina Specialistica, Diag-

nostica e Sperimentale, Università di Bologna, Bologna, Italy,

IRCCS

Azienda Ospedaliero‐Universitaria di Bologna Istituto di Ematologia

“Seràgnoli” and Diagnostica e Sperimentale Università di Bologna,

Dipartimento di Medicina Specialistica, Bologna, Italy,

The Royal

Marsden Hospital and The Institute of Cancer Research, Department of

Haemato‐Oncology, London, UK,

Copernicus Memorial Hospital ,

Department of Hematology , Lodz, Poland

CHU CAEN, Registre des

Hémopathies Malignes de Normandie Occidentale, CAEN CEDEX,

France,

The Institute of Cancer Research, Division of Molecular Pa-

thology, London, UK

Introduction. Cladribine is regarded as the ﬁrst treatment of choice

of symptomatic hairy cell leukemia (HCL) patients, as it is able to

provide high rates of response and very long duration of remission in

some cases.

Methods. Disease‐speciﬁc patients records have been reviewed at

four European centers of excellence in the treatment of HCL (Bologna,

Italy; Caen, France; London, United Kingdom, and Lodz, Poland) and all

patients requiring treatment who received frontline cladribine have

been extrapolated for analysis. Responses have been classiﬁed ac-

cording to the Consensus Resolution Criteria published in 1987. The

main study objectives were represented by long‐term overall survival

(OS), disease‐free survival (DFS) and progression‐free survival (PFS)

rates. PFS calculation involved all patients obtaining at least a partial

response; DFS was determined only in patients with a complete

response (CR) after treatment. Determining events for DFS and PFS

were disease progression (decline in hematologic parameters, reap-

pearance of marrow inﬁltration and/or organomegaly), initiation of a

subsequent treatment, death for any cause.

Results. Three hundred and eighty‐four HCL patients (including 3

patients with HCL variant) have been diagnosed and followed be-

tween 1969 and 2018, and all of them received frontline cladribine

(either subcutaneously or intravenously, according to era‐and site‐

speciﬁc guidelines and experience). A CR was obtained in 150

cases (39.1%), a partial response in 50 (13.0%) and a minor response

in 7 (1.8%). Two hundred and eight patients (54.2%) received no

further therapy besides cladribine as they did not require further

treatment for their disease. A continuous CR was documented in 76

patients (19.8%), at a median follow‐up period of 8.5 years (range, 1‐

22 years). Median OS was reached at 25.0 years, with 48.3% of pa-

tients being alive at 28 years. Median PFS was 13.0 years, with 43%

of patients being free of progression at 22 years. DFS was 26.5% at

22 years, with median reached at 11 years (Figure). Retreatment with

cladribine in relapsed patients occurred in 106 cases.

Conclusions. Cladribine is effective as frontline treatment of HCL and

may determine deep disease control in a signiﬁcant proportion of

cases, given that more than 50% of treated patients require no further

therapy. Good quality responses may be maintained for more than 20

years in nearly 40% of patients. Data obtained from this large inter-

national cohort of patients recapitulate the results obtained from

smaller single‐center clinical experiences with purine analogs.

Keywords: Lymphoid Cancers ‐Other

No conﬂicts of interest pertinent to the abstract.

FIGURE 1 Kaplan‐Meier curves in patients with grade 1, 2, and 3a. A. PFS on days of patents treated with R‐bendamustine theraphy; B.

PFS on days of patients treated with R‐CHOP theraphy. PFS Progression‐free survival

SUPPLEMENT ABSTRACTS

189

128 |MOLTO, A MULTICENTER, OPEN LABEL,

UNCONTROLLED, PHASE II CLINICAL TRIAL ON VENETOCLAX,

ATEZOLIZUMAB, OBINUTUZUMAB IN RICHTER

TRANSFORMATION: SAFETY INTERIM ANALYSIS

A. M. Frustaci

, A. Tedeschi

, P. L. Zinzani

, D. Pietrasanta

, M.

Coscia

, T. Zenz

, M. Motta

, G. Gaidano

, L. Scarfò

, M. Deodato

, G.

Zamprogna

, C. Vitale

, R. Cairoli

, D. Rossi

, M. Montillo

ASST Grande Ospedale Metropolitano Niguarda, Hematology, Milan,

Italy,

“L. e A. Seràgnoli,” University of Bologna, Hematology, Bologna,

Italy,

Azienda Ospedaliera SS Arrigo e Biagio e Cesare Arrigo,

Hematology, Alessandria, Italy,

A.O.U. Città della Salute e della Scienza di

Torino and Department of Molecular Biotechnology and Health Sciences,

University of Torino, Hematology, Torino, Italy,

University Hospital

Zürich and University of Zürich, Hematology, Zurich, Switzerland,

ASST

Spedali Civili, Hematology, Brescia, Italy,

University of Eastern Piedmont,

Translational Medicine, Division of Hematology, Novara, Italy,

Università

Vita‐Salute San Raffaele and IRCC Ospedale San Raffaele, Hematology,

Milano, Italy,

Oncology Institute of Southern Switzerland; Institute of

Oncology Research, Hematology, Bellinzona, Switzerland

Introduction: Diffuse large B‐cell (DLBCL) transformation from

chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma

(SLL), Richter Syndrome (RS), has poor prognosis. Single agent ven-

etoclax, as well as atezolizumab+/‐obinutuzumab showed activity in

heavily pretreated DLBCL. MOLTO is a multicenter international

phase II study (EUDRACT 2018‐005028‐40) evaluating venetoclax/

atezolizumab/obinutuzumab combination in 28 RS.

Methods: Treatment scheme: 35 cycles with obinutuzumab (1000 mg

C1‐8), atezolizumab (1200 mg C1‐18) and venetoclax (400 mg/diC1‐

35), in untreated DLBCL‐RS. At initial safety run phase 9 patients

(pts) received at least 3 courses with the possibility of premature

enrollment stop in case of ≥3 non‐infective/non‐hematologic

therapy‐related G ≥4 adverse events (AEs). Remaining pts received

same schedule of safety cohort.

Results: From October 2019, in the absence of safety warning

enrollment went on and, as of February 2021, 14 pts received at least

1 cycle. In table 1 are shown pts characteristics. Overall, 110 cycles

have been administered. Five serious AE (SAEs) were recorded in 4

pts: 1 fever of unknown origin (FUO) and 1 autoimmune encephalitis,

both G3, resolved and not leading to discontinuation, and 1 G5

pneumonia. The remaining 2 SAEs were related to hospitalization due

to disease progression (PD). Twelve/14 pts (85.7%) developed G≥1

AE of any grade. Severe (G 3‐5) hematological toxicity occurred in 7

pts, while 5 pts (including 2 developing SAEs) experienced severe

non‐hematological toxicity. The most common hematological toxicity

was thrombocytopenia: 20 episodes/110 courses (18.2%), 9 being

G≥3. Other G ≥3 hematologic toxicities: 10% neutropenia and 0.9%

anemia. Three severe non‐hematological toxicities were recorded: 1

hyperamylasemia; 1 hypercalcemia; 1 purpura. Seven pts (50%)

showed grade 2 FUO and only 1 major infection was observed. Two

were the AE of special interest: 1 autoimmune myositis and 1 auto-

immune encephalitis both successfully managed with steroids. No

G≥3 infusion related reactions (IRR) occurred and all G1/2 were

obinutuzumab‐related. All pts completed venetoclax ramp‐up, in 2

cases with accelerated dose‐escalation (Koening et al. 2020) due to

rapidly PD. No tumor lysis syndrome (TLS) was recorded. Overall, 9

pts are still on treatment with a median time on study of 4.4 (range 1

‐16.7) months, only 1/5 pts discontinued due to toxicity.

Conclusions: Treatment with venetoclax, obinutuzumab and atezo-

lizumab was well tolerated even in elderly, and the Independent Data

Monitoring Committee allowed the accomplishment of safety run

phase. Obinutuzumab‐atezolizumab combination did not result in an

enhanced IRR rate or severity. In this highly proliferating disease,

venetoclax did not lead to TLS even with the accelerated ramp‐up.

TABLE 1Patitent' characteristics

190

SUPPLEMENT ABSTRACTS

Accrual is ongoing, and updated results will be presented at the

meeting.

EA – previously submitted to EHA 2021.

The research was funded by: Hoffmann‐La Roche

Keywords: Aggressive B‐cell non‐Hodgkin lymphoma, Chronic Lym-

phocytic Leukemia (CLL), Combination Therapies

No conﬂicts of interest pertinent to the abstract.

129 |PIRTOBRUTINIB (LOXO‐305), A NEXT GENERATION

HIGHLY SELECTIVE NON‐COVALENT BTK INHIBITOR IN

PREVIOUSLY TREATED RICHTER TRANSFORMATION: RESULTS

FROM THE PHASE 1/2 BRUIN STUDY

W. Jurczak

, N. N. Shah

, N. Lamanna

, T. A. Eyre

, J. Woyach

, E.

Lech‐Maranda

, W. G. Wierda

, D. Lewis

, M. C. Thompson

, D.

Wang

, M. Yin

, M. Balbas

, B. C. Nair

, E. Y. Zhu

, D. E. Tsai

N. C. Ku

, C. C. Coombs

, A. R. Mato

Maria Sklodowska‐Curie National Research Institute of Oncology, Clin-

ical Oncology, Krakow, Poland,

Medical College of Wisconsin, Hematol-

ogy and Oncology, Brookﬁeld, USA,

Herbert Irving Comprehensive

Cancer Center, Columbia University, Medicine, New York, USA,

Oxford

University Hospitals NHS Foundation Trust, Churchill Cancer Center,

Haematology, Oxford, UK,

The Ohio State University Comprehensive

Cancer Center, Internal Medicine, Columbus, USA,

Institute of Hema-

tology and Transfusion Medicine, Hematology, Warsaw, Poland,

Anderson Cancer Center, Leukemia, Houston, USA,

Plymouth Hospitals

NHS Trust ‐Derriford Hospital, Haematology, Plymouth, UK,

Memorial

Sloan Kettering Cancer Center, Medicine, New York, USA,

Loxo

Oncology at Lilly, Statistics, Stamford, USA,

Loxo Oncology at Lilly,

Clinical, Stamford, CT, USA,

Loxo Oncology at Lilly, Medical, Stamford,

CT, USA,

University of North Carolina at Chapel Hill, Medicine, Chapel

Hill, USA

Introduction: Richter transformation (RT) is the development of an

aggressive large cell lymphoma in the setting of underlying CLL and is

a recurrent reason for treatment failure (5‐15%) among patients (pts)

receiving CLL directed therapy. Outcomes for pts with relapsed RT

are extremely poor, with no standard treatment and overall survival

estimated at 5‐8 months. Pirtobrutinib is a highly selective and

potent non‐covalent BTK inhibitor (BTKi) with high oral bioavail-

ability and a long half‐life, resulting in robust BTK target coverage

even in high‐grade malignancies with high BTK protein turnover.

Here we report the safety and efﬁcacy of pirtobrutinib in previously

treated pts with RT.

Methods: Pts with previously treated RT were enrolled to either the

dose escalation or expansion portion of the phase 1/2 BRUIN study

(NCT03740529). The primary endpoint for this analysis was ORR per

Lugano criteria. A key secondary endpoint was duration of response.

Efﬁcacy evaluable pts included all dosed RT pts who underwent their

ﬁrst response evaluation or discontinued therapy as of the data cut.

Results: As of 27 September 2020, 323 pts with B‐cell malignancies

were treated including 9 pts with previously treated RT (8 of 9 RT pts

received the RP2D of 200mg QD, 1 pt received 150mg QD). All 9 pts

had received ≥1 prior RT directed therapy, and the median number

of prior RT directed therapies was 2 (range 1‐5). Pts had received a

median of 4 prior lines of therapy for CLL (range 0‐6). Prior RT

directed therapies included chemoimmunotherapy (100%, n =9),

covalent BTKi (44%, n =4), anti‐PD‐1 or PD‐L1 antibody (33%, n =

3), mTOR inhibitor (22%, n =2), PI3K inhibitor (22%, n =2), CAR‐T

cell therapy (n =1), autologous stem cell transplant (n =1), polatu-

zumab vedotin (n =1), and pomalidomide (n =1). The ORR for the 8

efﬁcacy evaluable pts was 75% with 6 PR, 1 SD, and 1 NE. These pts

have been on treatment for 1.6, 2.3, 2.9+, 2.9+, 3.2+, 3.7, 6.4+, and

7.1+months (+indicates ongoing). The remaining pt continues on

treatment and is awaiting initial response assessment. No new safety

signals were identiﬁed in RT pts. Since data cut, 8 additional prior

treated pts with RT have been enrolled. Updated data with additional

follow‐up in all 17 RT pts will be presented.

Conclusion: Pirtobrutinib showed promising initial efﬁcacy in pts with

pretreated RT with extremely poor prognosis, including in pts who had

received prior chemoimmunotherapy and covalent BTK inhibitors.

EA – previously submitted to EHA 2021.

The research was funded by: Loxo Oncology at Lilly

Keywords: Aggressive B‐cell non‐Hodgkin lymphoma, Chronic

Lymphocytic Leukemia (CLL), Molecular Targeted Therapies

Conﬂicts of interests pertinent to the abstract

W. Jurczak

Research funding: Loxo Oncology, Janssen, AstraZeneca, Beigene

N. N. Shah

Other remuneration: Loxo Oncology

N. Lamanna

Research funding: Loxo Oncology

T. A. Eyre

Other remuneration: Loxo Oncology

J. Woyach

Other remuneration: Loxo Oncology

D. Wang

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

M. Yin

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

M. Balbas

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

B. C. Nair

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

SUPPLEMENT ABSTRACTS

191

E. Y. Zhu

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

D. E. Tsai

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

N. C. Ku

Employment or leadership position: Loxo Oncology at Lilly

Stock ownership: Loxo Oncology at Lilly

C. C. Coombs

Honoraria: Loxo Oncology

Research funding: Loxo Oncology

Other remuneration: Loxo Oncology

A. R. Mato

Consultant or advisory role: TG Therapeutics, Verastem

Research funding: Loxo Oncology, Genentech, Abbvie, AstraZeneca,

Adaptive, Pharmacyclics, Curio Sciences, Sunesis, Regeneron, Pﬁzer,

Aprea, Aptose, Verastem, and DTRM

Other remuneration: Loxo Oncology, Genentech, Abbvie, AstraZe-

neca, Adaptive, Pharmacyclics, and Curio Sciences

130 |PRELIMINARY RESULTS OF THE PHASE 2 STUDY OF

ZANUBRUTINIB IN PATIENTS WITH PREVIOUSLY TREATED B‐

CELL MALIGNANCIES INTOLERANT TO IBRUTINIB AND/OR

ACALABRUTINIB

M. Shadman

, J. P. Sharman

, M. Y. Levy

, R. Porter

, S. F. Zafar

, J. M.

Burke

, A. Chaudhry

, B. Freeman

, J. Misleh

, H. A. Yimer

, J. L.

Cultrera

, T. H. Guthrie

, E. Kingsley

, S. S. Rao

, D. Y. Chen

, X.

Zhang

, A. Idoine

, A. Cohen

, S. Feng

, J. Huang

, I. Flinn

Fred Hutchinson Cancer Research Center, University of Washington,

Clinical Research Division, Seattle, Washington, USA,

Willamette Valley

Cancer Institute and Research Center, Clinical Research Division, Eugene,

USA,

Texas Oncology‐Baylor Charles A. Sammons Cancer Center, Hema-

tology, Dallas, USA,

SSM Health Dean Medical Group, Hematology, Mad-

ison, USA,

Florida Cancer Specialists & Research Institute, Oncology, Fort

Myers, USA,

Rocky Mountain Cancer Centers, Oncology, Aurora, Colorado,

USA,

Summit Cancer Centers, Oncology, Spokane, USA,

Summit Medical

Group, Oncology, Florham Park, USA,

Medical Oncology Hematology

Consultants PA, Hematology, Newark, USA,

Texas Oncology‐Tyler,

Oncology, Tyler, USA,

Florida Cancer Specialists & Research Institute,

Oncology, Leesburg, USA,

GenesisCare, Oncology, Jacksonville, USA,

Comprehensive Cancer Centers of Nevada, Oncology, Las Vegas, USA,

Alpha Med Physicians Group, Oncology & Hematology, Tinley Park, USA,

BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., Hema-

tology, San Mateo, USA,

Sarah Cannon Research Institute/Tennessee

Oncology, Oncology, Nashville, USA

Introduction: Many patients (pts) with B‐cell malignancies require

continuous treatment with Bruton tyrosine kinase inhibitors (BTKi).

Adverse events (AEs) are a common reason for ibrutinib (ibr) or

acalabrutinib (acala) discontinuation. Early data from BGB‐3111‐215

showed zanubrutinib (zanu) was well tolerated in pts with B‐cell

malignancies who were intolerant to either ibr or acala. Here we

report preliminary results of the BGB‐3111‐215 trial, with a median

follow‐up of 4.2 months.

Methods: Pts meeting protocol criteria for intolerance to ibr, acala, or

both (without documented progressive disease) were given

zanu monotherapy (160 mg twice daily or 320 mg once daily). Recur-

rence of AEs that led to intolerance of prior BTKi and additional safety

measures were assessed based on the Common Terminology Criteria

for AEs v5.0. Investigators determined responses using disease status

at study entry as baseline and established disease criteria.

Results: As of November 1, 2020 (cutoff), 44 pts (n =34 chronic

lymphocytic leukemia/small lymphocytic lymphoma, n =6 Walden-

ström macroglobulinemia, n =2 mantle cell lymphoma, n =2 marginal

zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed

for safety. The median age was 70.5 y (range, 49‐91); median duration

of treatment was 4.2 months (range, 0.1‐12.6). The median number of

prior regimens was 2 (range, 1‐12). Regarding prior BTKi, 39 pts

received ibr only, 4 received ibr and acala, and 1 received acala only.

The median number of ibr‐or acala‐intolerant AEs per pt was 2 (range,

1‐5). 83% of ibr‐and 78% of acala‐intolerant events did not recur on

zanu; Table. At cutoff, 43 pts remained on treatment; 1 withdrew

consent due to zanu‐unrelated grade 3 syncope. Overall, 34 pts

(77.3%) reported any AE; most commonly reported AEs were myalgia

(n =9; 20.5%), contusion (n =8; 18.2%), dizziness (n =7; 15.9%), fatigue

(n =7; 15.9%), and cough (n =5; 11.4%). Grade ≥3 AEs were reported in

6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and sal-

monella infection), AEs requiring dose interruptions in 6 pts (13.6%),

and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu

discontinuation. No deaths were reported. All efﬁcacy evaluable pts

(26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16

[61.5%]) of their response.

Conclusions: Zanu provided an additional treatment option after

intolerance to other BTKi, demonstrating tolerability and sustained

or improved efﬁcacy. Updated results will be presented.

EA – previously submitted to ASCO and EHA 2021.

The research was funded by: BeiGene (Beijing) Co., Ltd., Beijing,

China and BeiGene USA, Inc., San Mateo, CA, USA

Keywords: Chronic Lymphocytic Leukemia (CLL)

Conﬂicts of interests pertinent to the abstract

M. Shadman

Consultant or advisory role: AbbVie, Genentech, AstraZeneca,

SoundBiologics, Pharmacyclics, Verastem, ADC Therapeutics, Bei-

Gene, Cellectar, Bristol Myers Squibb, Morphosys, TG Therapeutics,

InnatePharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, and

AtaraBiotherapeutics

Research funding: Mustang Bio, Celgene, Bristol Myers Squibb,

Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, Bei-

Gene, AstraZeneca, Sunesis

192

SUPPLEMENT ABSTRACTS

J. P. Sharman

Employment or leadership position: US Oncology Network

Consultant or advisory role: Pharmacyclics, Celgene, TG Therapeu-

tics, Genentech, AbbVie, Acerta Pharma/AstraZeneca, BeiGene,

Pﬁzer, Bristol Myers Squibb

Stock ownership: VelosBio

Research funding: Pharmacyclics, Genentech, Celgene, Acerta

Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck,

Takeda

M. Y. Levy

Employment or leadership position: Baylor University Med Center

Consultant or advisory role: BeiGene

Research funding: BeiGene

Other remuneration: Speakers' Bureau: BeiGene, AbbVie, Amgen,

AstraZeneca, BeiGene, Bristol Meyers Squibb, Dova, Epizyme, Gilead,

GSK, Janssen, Jazz, Karyopharm, Morphosys, Sanoﬁ, Seattle Ge-

netics, Takeda

S. F. Zafar

Employment or leadership position: Florida Cancer Specialists +

Research Institute

Honoraria: Karyopharm, AstraZeneca, Bristol Meyers Squibb

Research funding: Sarah Canon Research Institute

Educational grants: AstraZeneca, Bristol Meyers Squibb

J. M. Burke

Consultant or advisory role: Genentech/Roche, AbbVie, Seattle Ge-

netics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem,

MorphoSys, Kura Oncology, Epizyme, BeiGene, Kymera, Novartis

Other remuneration: Speakers' Bureau: Seattle Genetics, BeiGene

A. Chaudhry

Consultant or advisory role: Bayer

Stock ownership: Novartis

Honoraria: Bayer

H. A. Yimer

Employment or leadership position: Texas Oncology

Consultant or advisory role: AstraZeneca, Amgen, Karyopharm

Stock ownership: Epizyme, Karyopharm

Research funding: Janssen, BeiGene

Educational grants: Janssen, AstraZeneca, BeiGene, Karyopharm,

Amgen

Other remuneration: Speakers' Bureau: Janssen, AstraZeneca, Bei-

Gene, Karyopharm, Amgen, Takeda

J. L. Cultrera

Employment or leadership position: Florida Cancer Specialists and

Research Institute

Research funding: BeiGene, Takada, Genentech, Merck, Acerta, Eli

Lilly, AstraZeneca, Bristol Meyers Squibb, EMD Serono, Seattle

Genetics

Other remuneration: Speakers' Bureau: Celgene, Amgen, Aurobindo

Pharma

T. H. Guthrie

Employment or leadership position: Genesis Care LTD

D. Y. Chen

Employment or leadership position: BeiGene

Stock ownership: BeiGene

X. Zhang

Employment or leadership position: BeiGene

Stock ownership: BeiGene

A. Idoine

Employment or leadership position: BeiGene

Stock ownership: BeiGene

A. Cohen

Employment or leadership position: BeiGene

Stock ownership: BeiGene

S. Feng

Employment or leadership position: BeiGene

Stock ownership: BeiGene, Amgen, Nektar, Illumina, Annexon,

Hutchison China MediTech

Other remuneration: Patents, Royalties, OtherIntellectual Property:

BeiGene USA Inc.

J. Huang

Employment or leadership position: BeiGene

Consultant or advisory role: BeiGene

Stock ownership: BeiGene

Educational grants: BeiGene

I. Flinn

Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Gilead

Sciences, Great Point Partners, Iksuda Therapeutics, Janssen, Juno

Therapeutics, Kite Pharma, MorphoSys, Nurix Therapeutics, Phar-

macyclics, Roche, Seattle Genetics, Takeda, Unum Therapeutics,

Verastem, Yingli Pharmaceuticals

Recurrence and Severity Chage of AEs Leading of lbr or Acala Intolearnce

SUPPLEMENT ABSTRACTS

193

Research funding: AbbVie, Acerta Pharma, Agios, ArQule, AstraZe-

neca, BeiGene, Calithera Biosciences, Celgene, Constellation Phar-

maceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech,

Gilead Sciences, IGM Biosciences, Incyte, Inﬁnity Pharmaceuticals,

Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma,

Loxo, Merck, MorphoSys, Novartis, Pﬁzer, Pharmacyclics, Portola

Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics,

Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase

Research & Development Corp., Unum Therapeutics, Verastem

131 |UPDATED EFFICACY AND SAFETY RESULTS OF

ORELABRUTINIB IN THE TREATMENT OF RELAPSED OR

REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL CELL

LEUKEMIA

W. Xu

, Y. Song

, T. Wang

, S. Yang

, L. Liu

, Y. Hu

, W. Zhang

, J.

Zhou

, S. Gao

, K. Ding

, H. Zhang

, Z. Zhu

, S. Wang

, B. Xu

, J.

, T. Liu

, C. Ji

, Z. Xia

, Y. Li

, X. Wang

, R. Zhao

, B.

Zhang

, J. Li

Pukou CLL Center, The First Afﬁliated Hospital of Nanjing Medical

University, Jiangsu Province Hospital, Collaborative Innovation Center for

Cancer Personalized Medicine, Hematology Department, Nanjing, China,

Afﬁliated Cancer Hospital of Zhengzhou University, Hematology

Department, Zhengzhou, China,

National Clinical Research Center for

Blood Disease, State Key Laboratory of Experimental Hematology, Blood

Disease Hospital and Institute of Hematology, Chinese Academy of

Medical Sciences & Peking Union Medical College, Lymphoma Center,

Tianjin, China,

Peking University People's Hospital, Hematology

Department, Beijing, China,

The Fourth Hospital of Hebei Medical

University, Hematology Department, Shijiazhuang, China,

Union

Hospital, Tongji Medical College, Huazhong University of Science and

Technology, Hematology Department, Wuhan, China,

Peking Union

Medical College Hospital, Hematology Department, Beijing, China,

Tongji

Hospital Huazhong University of Science and Technology, Hematology

Department, Wuhan, China,

The First Hospital, Jilin University,

Hematology Department, Jilin, China,

The First Afﬁliated Hospital of

University of Science and Technology of China, Hematology Department,

Hefei, China,

Tianjin Medical University Cancer Institute & Hospital,

Lymphoma, Tianjin, China,

Henan Provincial People's Hospital,

Hematology Department, Zhengzhou, China,

Guangzhou First People's

Hospital, Hematology Department, Guangzhou, China,

The First

Afﬁliated Hospital of Xiamen University, Hematology Department,

Xiamen, China,

Fujian Medical University Union Hospital, Fujian

Institute of Hematology, Fujian Provincial Key Laboratory on Hematology,

Hematology Department, Fuzhou, China,

West China Hospital Sichuan

University, Hematology Department, Chengdu, China,

Qilu Hospital,

Cheeloo College of Medicine, Shandong University, Hematology

Department, Jinan, China,

Sate Key Laboratory of Oncology in South

China, Collaborative Innovation of Cancer Medicine, Sun Yat‐sen Uni-

versity Cancer center, Department of Hematologic Oncology, Guangzhou,

China,

The First Afﬁliated Hospital of China Medical University, He-

matology Department, Shenyang, China,

School of Medicine, Shandong

University, Hematology, Jinan, China,

Beijing InnoCare Pharma Tech

Co., Ltd, Beijing, China,

Beijing InnoCare Pharma Tech Co., Ltd, Beijing,

China

Introduction: Orelabrutinib is a novel and highly selective irrevers-

ible BTK inhibitor. We previously reported that orelabrutinib had

high bioavailability with ∼100% BTK occupancy at 24 hours at 150

mg daily dosing regimen and had demonstrated excellent safety and

efﬁcacy proﬁles in a phase II trial of r/r CLL/SLL. Here we present an

updated result following the extended time of treatment.

Method: This is an open‐label, multicenter, phase II study to evaluate

the safety and efﬁcacy following an oral daily administration of

orelabrutinib. Responses were assessed per 2008 IWCLL criteria.

Results: A total of 80 patients with r/r CLL/SLL were enrolled.

Eligible patients received ≥1 prior treatment with median age of 60.0

years. There are 70% of patients for Rai stage 3‐4 disease, 22.5% for

del(17p) and/or TP53 mutation, 41.3% for unmutated IGHV and

23.8% for del(11q). The median follow‐up time was 25.6 months, with

71.3% remaining on study treatment.

The efﬁcacy results were evaluated by both IRC and in-

vestigators, with the ORR of 92.5 % with 16.3% CR/CRi, 65.0% PR

and 11.3% PR‐L by IRC, and the ORR of 93.8% with 21.3% CR/CRi,

61.3% PR, and 11.3% PR‐L by investigators. These results revealed

high concordance rate for overall response assessments between

IRC and investigator. Median time for achieving ﬁrst response was

1.87 months. The median DOR and PFS were not reached. The

estimated 18‐month DOR was 77.2%, and PFS was 78.7% by IRC.

The ORR was 100% in patients with Del(17p) and/or TP53 mutation.

The ORR was 94.7% for Del(11q)) and 93.9% for unmutated IGHV.

Comparing to the previous CR/CRi rate of 8.8% and 10.0% reported

at median follow up of 14.3 months, the updated CR/CRi rate had

achieved 21.3% and 16.3% by investigator and IRC assessment,

respectively. Orelabrutinib showed a signiﬁcant higher CR/CRi rate

in r/r CLL/SLL comparing to other BTK inhibitors at a similar median

follow‐up period.

Extended follow‐up analysis did not reveal new safety nor

toxicity concerns. Similar to the previous reported safety results,

most AEs were mild to moderate. The most frequent AEs were he-

matological toxicities, upper respiratory tract infection, pneumonia

and hypokalemia. No case of atrial ﬁbrillation nor secondary malig-

nancy was reported, no patient was observed for ≥3 grade hyper-

tension and only one patient had ≥3 grade diarrhea. Major

hemorrhage was reported in 2 patients, one with intracranial hem-

orrhage (65‐year old patient with >10 years hypertension) and the

other with vitreous hemorrhage which was assessed as unlikely

related to the treatment of orelabrutinib.

Conclusion: This updated study result further conﬁrms that orelab-

rutinib is efﬁcacious in treating r/r CLL patients with a signiﬁcant

higher CR rate, durable response and improved safety proﬁles. Ore-

labrutinib provides a favorable therapeutic choice for patients with r/r

CLL/SLL and a potential best candidate for the combination therapy.

EA – previously submitted to regional or national meetings (up to

1000 attendees)

194

SUPPLEMENT ABSTRACTS

The research was funded by: Beijing InnoCare Pharma Tech Co., Ltd

Keywords: Chronic Lymphocytic Leukemia (CLL)

Conﬂicts of interests pertinent to the abstract

R. Zhao

Employment or leadership position: Employment

B. Zhang

Employment or leadership position: Employment

132 |SAFETY AND EFFECTIVENESS OF VENETOCLAX

MONOTHERAPY IN ELDERLY PATIENTS WITH RELAPSED/

REFRACTORY CLL UNDER REAL‐LIFE CONDITIONS – DATA

FROM THE OBSERVATIONAL STUDY VERVE

I. Schwaner

, H. Hebart

, C. Losem

, T. Wolff

, J. Huelsenbeck

, B.

Schmidt

, D. Rossi

, T. Noesslinger

Onkologie Kurfürstendamm, Berlin, Germany , Hematology/Oncology,

Berlin, Germany,

Kliniken Ostalb, Hematology/Oncology, Mutlangen,

Germany,

MVZ Onkologie und Hämatologie , Hematology/Oncology,

Neuss, Germany,

Onkologie Lerchenfeld, Hematology/Oncology,

Hamburg, Germany,

AbbVie Deutschland GmbH & Co. KG, Hematology/

Oncology, Wiesbaden, Germany,

Hämatologisch‐Onkologische

Gemeinschaftspraxis, Hematology/Oncology, Munich, Germany,

Institute

of Oncology Research, Hematology/Oncology, Bellinzona, Switzerland,

Medizinische Abteilung für Hämatologie und Onkologie, Hanusch

Krankenhaus, Hematology/Oncology, Vienna, Austria

Background: In clinical trials, treatment of chronic lymphocytic

leukaemia (CLL) with venetoclax (Ven) has shown promising efﬁcacy

and good tolerability. However, patients treated in clinical trial

often represent a selected group not representative for patients

treated in daily practice. Prospective real‐world data on Ven usage

are limited.

Aim: We conduct a prospective non‐interventional observational

study assessing effectiveness, safety, and quality of life in relapsed/

refractory patients (RR) treated with Ven in Austria, Germany, and

Switzerland. The population enrolled is representative for patients

treated with Ven according to local label. This report focuses on

patients treated with Ven monotherapy.

Methods: Adult patients with CLL requiring therapy treated with Ven

according to local label are eligible for the study. Patients’ visits are

scheduled at the physician's discretion and according to clinical

practice. Study documentation is possible at baseline, weekly during

ramp‐up, monthly until the end of 6 months and 3‐monthly after-

wards up to a maximum of 3 years. Response assessment according

to IwCLL criteria can be documented at the end of ramp‐up, after 3,

12, and 24 months.

Results: Until November 15th, 2020, 62 patients were enrolled, 57

had received at least one dose of Ven (=safety population), and for

43 treatment response had been documented at least once (=effec-

tiveness population). Median age was 75 years, 64% of patients were

male, 69% had at least one comorbidity, most commonly cardiovas-

cular (45%), 61% received comedication. Patients were pre‐treated

with a median of 2 (range 1‐10) lines of therapy, i.e., chemo‐

immuno‐therapy (69%) and therapy with B‐cell receptor inhibitors

(81%). Del(17p), TP53 mutation, and presence of unmutated IGHV

had been diagnosed in 37%, 35%, and 29%, respectively (excl. missing

data: 43%, 45%, 70%).

With a median observation time of 210 (range 1‐879) days, 93% of

patients experienced at least one AE, 63% CTCAE grade 3/4 AEs, SAEs

40%. There were four grade 5 AEs reported. The most common AEs in

any grade were thrombocytopenia, diarrhoea, neutropenia (23%, 21%,

15%). The median for progression‐free survival (PFS) and overall sur-

vival (OS) has not been reached, the 12‐month estimates were 72%

(PFS) and 78,2% (OS). At 6 and 12 months, an estimated 67,6 and

60,0%, respectively, remain on therapy. The reported best overall

response at 12 months was 67,4% (CR+CRi 32,6%; PR: 34,8%).

Conclusion: Under real‐world conditions, Ven monotherapy is used

in elderly R/R CLL patients. The treatment was well tolerated. Pa-

tients presented with high‐risk features, e.g. del17p or BCRi pre-

treatment; yet, the response rate was high and the proportion of

patients with deep response increased over time. Our study conﬁrms

ﬁndings from Venetoclax Phase‐II‐studies in R/R CLL patients

treated under real‐world conditions.

The research was funded by: AbbVie sponsored this study and

contributed to the design, study conduct, and analysis. AbbVie

participated in the interpretation of data, review, and approval of the

abstract. No honoraria or payments were made for authorship.

All authors had access to all relevant data.

Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted

Therapies

Conﬂicts of interests pertinent to the abstract

I. Schwaner

Honoraria: Abbvie, Amgen, AstraZeneca, Celgene, Janssen, Novartis,

Roche, Servier

H. Hebart

Consultant or advisory role: AbbVie, AstraZeneca, Celgene, Janssen,

Roche

T. Wolff

Honoraria: Novartis, Celgene, Roche, Bayer, Teva, AbbVie

Research funding: Novartis, Celgene, Roche, Bayer, Teva, AbbVie

J. Huelsenbeck

Employment or leadership position: AbbVie

Stock ownership: AbbVie

B. Schmidt

Consultant or advisory role: AbbVie, Incyte, Novartis, Sanoﬁ‐Aventis,

Alexion, Biotest, Takeda, Janssen

D. Rossi

Honoraria: Abbvie, AstraZeneca, Gilead, Janssen, Verastem, Roche,

Cellestia

SUPPLEMENT ABSTRACTS

195

Research funding: Abbvie, AstraZeneca, Gilead, Janssen, Verastem,

Roche, Cellestia

T. Noesslinger

Consultant or advisory role: AbbVie, Celgene, Roche, Janssen,

AstraZeneca, Gilead

133 |IBRUTINIB TOLERABILITY AND OUTCOME IN PATIENTS

WITH HIGH‐RISK CHRONIC LYMPHOCYTIC LEUKEMIA

A. Condoluci

, L. Terzi‐di‐Bergamo

, G. Forestieri

, R. Moia

, C.

Deambrogi

, M. Deodato

, A. M. Frustaci

, M. Merli

, R. Mattar-

ucchi

, F. Autore

, G. Fahrni

, L. Scarfò

, D. Gussetti

, P. Bulian

, A.

Zanatta

, V. Spina

, M. R. Faderl

, A. Bruscaggin

, K. Pini

, D. Pif-

faretti

, R. Koch

, M. C. Pirosa

, M. G. Cittone

, J. Passweg

, F.

Cavalli

, E. Zucca

, B. Gerber

, S. Gillessen

, G. Stüssi

, V. Gattei

P. Ghia

, M. Gregor

, L. Laurenti

, F. Passamonti

, A. Tedeschi

, G.

Gaidano

, D. Rossi

Oncology Institute of Southern Switzerland, Clinic of Hematology,

Bellinzona, Switzerland,

Institute of Oncology Research, Laboratory of

Experimental Hematology, Bellinzona, Switzerland,

University of Eastern

Piedmont, Department of Translational Medicine, , Division of

Hematology, Novara, Italy,

ASST Grande Ospedale Metropolitano

Niguarda, Niguarda Cancer Center, Department of Hematology, Milan,

Italy,

University of Insubria, Ospedale di Circolo e Fondazione Macchi,

Department of Hematology, Varese, Italy,

Fondazione Policlinico

Universitario A. Gemelli, Catholic University of the Sacred Hearth,

Hematology Institute, Rome, Italy,

Cantonal Hospital Lucerne, Division of

Haematology and Central Haematology Laboratory, Lucerne, Switzerland,

IRCCS San Raffaele Scientiﬁc Institute and Vita‐Salute San Raffaele

University, Strategic Research Program on CLL, Division of Experimental

Oncology, Milan, Italy,

Centro di Riferimento Oncologico di Aviano

(CRO), IRCCS, Clinical and Experimental Onco‐Hematology Unit, Aviano,

Italy,

University Hospital Basel, Department of Haematology, Basel,

Switzerland,

Università della Svizzera Italiana, Institute of Oncology

Research, Bellinzona, Switzerland,

Oncology Institute of Southern

Switzerland, Clinic of Oncology, Bellinzona, Switzerland

Background: Overall, ten independent retrospective studies

addressed the question of the tolerability of ibrutinib in the real‐

world setting. Discontinuation rates ranged from 5% to 29%. Such

heterogeneity may reﬂect differences in the case mix, follow up and

accessibility to next treatments. Dose reduction/transient interrup-

tion rates ranged from 22% to 32%. The impact of intolerance on

ibrutinib effectiveness according to baseline CLL biology is largely

unknown. We assessed whether outcomes of patients with high‐risk

CLL is affected by ibrutinib discontinuation, interruption, or dose

reduction due to intolerance.

Methods: The IOSI‐EMA‐001 and the IOSI‐EMA‐003 observational

prospective studies (NCT02827617; NCT03280394) enrolled pa-

tients with CLL treated with ibrutinib according to prescribing in-

dications in Switzerland and Italy. Pre‐treatment demographics,

disease data, mutation analysis by LyV4.0 CAPP‐seq assay, infor-

mation on treatment discontinuation, interruption and dose reduc-

tion, and efﬁcacy outcomes were collected.

Results: In stotal, 90 patients were included in the per protocol

population. Baseline features include age >65 years in 71% of cases,

male gender in 61%, previous treatment in 47%, beta‐2‐

microglobulin >5 mg/L in 40%, lactate dehydrogenase >ULN in

55%, TP53 disruption in 83%, and unmutated IGHV in 78%. Baseline

mutations of SF3B1 (30%), NOTCH1 (28%), ATM (15%), EGR2 (13%),

196

SUPPLEMENT ABSTRACTS

MGA (11%), POT1 (11%), and BIRC3 (10%) were reported in ≥10% of

cases. The median follow‐up of patients was 2.8 years. Median time

on ibrutinib was 29 months. Discontinuation of ibrutinib due to any

reason except progressive disease (PD) was reported in 21% of pa-

tients and their median time on ibrutinib was 17 months. Median

time to discontinuation due to any reason except PD was 16 months.

At least 1 interruption was reported in 31% of patients, and 6%

interrupted treatment >1 time. The median consecutive days of

interruption was 28 and the median total days of interruption was

38. Dose reduction was required by 25% of patients, including 5%

who reduced to 140 mg/d. Median dose intensity (proportion of

administered vs planned doses of ibrutinib 420 mg/d) was 93.4%.

Three‐years PFS of the per protocol cohort was 80.3% (CI 69.9‐92.2).

Early discontinuation due to any reason except PD, treatment

interruption, regardless of duration (≥1, ≥8, ≥14 and ≥21 consecu-

tive days), and dose reduction had no impact on PFS. By recursive

partitioning, PFS stratiﬁcation based on the best cut‐off for dose

intensity did not show a negative outcome, indicating no com-

pounded effect of both dose reduction and interruption.

Conclusions: Ibrutinib treatment modiﬁcations seem not to have

major impact on PFS in patients with high‐risk CLL. The impact of

ibrutinib dose intensity during the ﬁrst months of therapy on PFS,

and the impact of ibrutinib tolerability on time to next treatment will

be explored in this dataset.

Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-

nostic Biomarkers, Ongoing Trials

Conﬂicts of interests pertinent to the abstract

E. Zucca

Honoraria: AbbVie; AstraZeneca; Janssen

Research funding: AbbVie; AstraZeneca; Janssen

D. Rossi

Honoraria: AstraZeneca; AbbVie; Janssen

Research funding: AstraZeneca; AbbVie; Janssen

134 |EFFICACY AND DISCONTINUATION RATE OF IBRUTINIB

IN TREATMENT NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA

PATIENTS WITH TP53 ABNORMALITIES. A REAL‐LIFE CAMPUS

CLL STUDY

A. Visentin

, F. R. Mauro

, F. Cibien

, C. Vitale

, G. Reda

, A. Fresa

, S.

Ciolli

, D. Pietrasanta

, M. Marchetti

, R. Murru

, M. Gentile

, G. M.

Rigolin

, F. M. Quaglia

, L. Scarfò

, P. Sportoletti

, S. Pravato

, L.

Romano Gargarella

, M. Facco

, F. Piazza

, M. Marchetti

, M. Coscia

L. Laurenti

, S. Molica

, G. Pizzolo

, R. Foà

, A. Cuneo

, L. Trentim

Hematology and Clinical Immunology Unit, Department of Medicine,

University of Padova, Padova, Italy,

Hematology Unit, Department of

Translational and Precision Medicine, "Sapienza" University, Rome, Italy,

Hematology Unit, Ca’ Foncello Hospital, Treviso, Italy,

Department of

Molecular Biotechnology and Health Sciences, , University of Torino and

Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino,

Torino, Italy,

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale

Maggiore, Milan, Italy,

Hematology Institute, Fondazione Policlinico

Universitario Agostino Gemelli IRCSS, Roma, Italy,

Hematology Unit,

Careggi Hospital, University of Florence, Florence, Italy,

Division of

Hematology, A.O. SS Antonio e Biagio and Cesare Arrigo, Alessandria,

Italy,

Hematology and Stem Cell Transplantation Unit, Ospedale A.

Businco, ARNAS “G. Brotzu”, Cagliari, Italy,

Hematology unit,

Department of Hemato‐Oncology, Annunziata Hospital, Cosenza, Italy,

Hematology section, Department of Medical Sciences, Azienda

Ospedaliera‐Universitaria, Arcispedale S. Anna, University of Ferrara,

Ferrara, Italy,

Department of Medicine, Section of Hematology, Uni-

versity of Verona & Azienda Ospedaliera Universitaria Integrata, Verona,

Italy,

Strategic program on CLL, University health and Science “San

Raffaele”, Milan, Italy,

Hematology and Clinical Immunology unit, Uni-

versity of Perugia, Perugia, Italy,

Department Hematology‐Oncology,

Azienda Ospedaliera Pugliese‐Ciaccio, Catanzaro, Italy

Backgroung: Disruption of the TP53 gene, including 17p13 deletion

(17p‐) and/or TP53 mutation (TP53m), is a negative prognostic

biomarker in chronic lymphocytic leukemia (CLL). Ibrutinib has

proven to be highly active in CLL with unfavorable features, but data

on treatment‐naive (TN) patients with TP53 abnormalities (abn)

derive from almost 90 patients included in 5 clinical trials.

The aim of this study is to describe the efﬁcacy and discontinu-

ation rate of ibrutinib in TN CLL patients with TP53 abn in the real‐

life setting.

Methods: Medical charts of CLL patients followed in 14 centers

belonging to the Italian Campus CLL network were retrospectively

reviewed to identify CLL with 17p‐(cut‐off 10%) and/or TP53m

treated front‐line with ibrutinib. The primary endpoint was the rate

of discontinuation. Secondary endpoints were progression‐free sur-

vival (PFS), time‐to‐next treatment (TTNT), overall survival (OS).

Response assessment was done according to the iwCLL 2018

guidelines.

Results: One hundred TN CLL patients were recruited in this study.

Fifty‐one patients were male, the median age at the start of ibrutinib

was 71 years (range 37‐87), including 35 octogenarians, the median

CIRS was 4 (range 0‐13), 42 had a creatinine clearance <60ml/min.

Seventy‐seven patients were IGHV unmutated, 33 displayed only

17p‐, 22 only TP53m and 45 both 17p‐and TP53m.

The overall response rate was 84%, including 10% of complete

remissions. After a median follow‐up of 24 months, 13 patients

relapsed, 10 required further therapy, 2 developed a Richter syn-

drome (RS) and 8 died (4 infections, 1 melanoma, 1 RS, 1 sudden

death). The median PFS, TTNT and OS have not been not reached.

The 12, 24 and 36‐month PFS was 91%, 82% and 75%, respectively.

The 12, 24 and 36‐month TTNT was 94%, 89% and 82%. The 12, 24

and 36‐month OS was 96%, 92% and 87% (Figure 1A). PFS was

shorter in patients ≥75 years (2‐yy PFS 69% vs 89%, p =0.04), who

did not respond (85% vs 66%, p =0.03) but was not inﬂuenced by

IGHV status.

Twenty‐eight patients discontinued treatment, 20 for adverse

events (AE) (8 infections, 5 atrial ﬁbrillations, 4 others and 3 deaths),

SUPPLEMENT ABSTRACTS

197